U.S. patent application number 17/278930 was filed with the patent office on 2022-02-10 for liquid polymer delivery system for extended administration of drugs.
The applicant listed for this patent is TOLMAR INTERNATIONAL, LTD.. Invention is credited to Garrett Shane GLOVER, John Charles MIDDLETON, Avinash NANGIA, Amy Haller VAN HOVE.
Application Number | 20220040201 17/278930 |
Document ID | / |
Family ID | |
Filed Date | 2022-02-10 |
United States Patent
Application |
20220040201 |
Kind Code |
A1 |
VAN HOVE; Amy Haller ; et
al. |
February 10, 2022 |
LIQUID POLYMER DELIVERY SYSTEM FOR EXTENDED ADMINISTRATION OF
DRUGS
Abstract
Liquid polymer pharmaceutical compositions comprising a
biodegradable liquid polymer, a biocompatible solvent system, and
an active pharmaceutical ingredient (API) are disclosed. The
compositions of the invention are useful for providing extended,
long-term release of the API.
Inventors: |
VAN HOVE; Amy Haller; (Fort
Collins, CO) ; GLOVER; Garrett Shane; (Fort Collins,
CO) ; MIDDLETON; John Charles; (Fort Collins, CO)
; NANGIA; Avinash; (Fort Collins, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TOLMAR INTERNATIONAL, LTD. |
Dublin 2 |
|
IE |
|
|
Appl. No.: |
17/278930 |
Filed: |
September 24, 2019 |
PCT Filed: |
September 24, 2019 |
PCT NO: |
PCT/IB2019/001056 |
371 Date: |
March 23, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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62736182 |
Sep 25, 2018 |
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International
Class: |
A61K 31/568 20060101
A61K031/568; A61K 9/00 20060101 A61K009/00; A61K 47/34 20060101
A61K047/34; A61K 47/22 20060101 A61K047/22; A61K 47/10 20060101
A61K047/10; A61K 47/14 20060101 A61K047/14 |
Claims
1.-82. (canceled)
83. A pharmaceutical composition, comprising: an active
pharmaceutical ingredient having a log P of at least about 0; a
biocompatible solvent or combination or mixture of solvents and/or
co-solvents; and a biodegradable liquid polymer, wherein the active
pharmaceutical ingredient is in a substantially solid form in the
biodegradable liquid polymer and the biocompatible solvent or
combination or mixture of solvents and/or co-solvents at body
temperature, and wherein the active pharmaceutical ingredient has a
D.sub.v,50 of between about 1 .mu.m and about 250 .mu.m and a
particle size span of between about 1 and about 8.
84. The pharmaceutical composition of claim 83, wherein the active
pharmaceutical ingredient is in a substantially solid form in the
biodegradable liquid polymer and the biocompatible solvent or
combination or mixture of solvents and/or co-solvents at
temperatures up to between about body temperature to at least about
45.degree. C.
85. The pharmaceutical composition of claim 83, wherein the active
pharmaceutical ingredient is a hydrophobic small molecule organic
compound having a log P of at least about 2.5 or a pharmaceutically
acceptable salt, ester, hydrate, solvate, or prodrug thereof.
86. The pharmaceutical composition of claim 83, wherein the active
pharmaceutical ingredient has a D.sub.v,50 of between about 15
.mu.m and about 200 .mu.m.
87. The pharmaceutical composition of claim 83, wherein the active
pharmaceutical ingredient has a D.sub.v,50 of between about 50
.mu.m and about 150 .mu.m.
88. The pharmaceutical composition of claim 83, wherein the active
pharmaceutical ingredient has a particle size span of between about
2 and about 6.
89. The pharmaceutical composition of claim 83, wherein the
biocompatible solvent or combination or mixture of solvents and/or
co-solvents is selected from the group consisting of acetone,
butyrolactone, .epsilon.-caprolactone, N-cycylohexyl-2-pyrrolidone,
diethylene glycol monomethyl ether, dimethyl acetamide, dimethyl
formamide, dimethyl sulfoxide (DMSO), ethyl acetate, ethyl lactate,
N-ethyl-2-pyrrolidone, glycerol formal, glycofurol,
N-hydroxyethyl-2-pyrrolidone, isopropylidene glycerol, lactic acid,
methoxypolyethylene glycol, methoxypropylene glycol, methyl
acetate, methyl ethyl ketone, methyl lactate,
N-methyl-2-pyrrolidone (NMP), low-molecular weight (MW)
polyethylene glycol (PEG), polysorbate 80, polysorbate 60,
polysorbate 40, polysorbate 20, polyoxyl 35 hydrogenated castor
oil, polyoxyl 40 hydrogenated castor oil, sorbitan monolaurate,
sorbitan monostearate, sorbitan monooleate, benzyl alcohol,
n-propanol, isopropanol, tert-butanol, propylene glycol,
2-pyrrolidone, .alpha.-tocopherol, triacetin, tributyl citrate,
acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate,
esters thereof, and combinations and mixtures thereof.
90. The pharmaceutical composition of claim 83, wherein the
biocompatible solvent or combination or mixture of solvents and/or
co-solvents comprises a biocompatible solvent in combination with a
low-molecular weight (MW) polyethylene glycol (PEG).
91. The pharmaceutical composition of claim 83, wherein the
biocompatible solvent or combination or mixture of solvents and/or
co-solvents is selected from the group consisting of: dimethyl
sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), a low-molecular
weight (MW) polyethylene glycol (PEG), and combinations and
mixtures thereof.
92. The pharmaceutical composition of claim 91, wherein a ratio of
PEG to NMP or DMSO is between about 20:80 and about 80:20.
93. The pharmaceutical composition of claim 83, wherein the
biodegradable liquid polymer comprises lactide residues and one or
both of .epsilon.-caprolactone residues and trimethylene carbonate
residues.
94. The pharmaceutical composition of claim 83, the biodegradable
liquid polymer comprises lactide and .epsilon.-caprolactone
residues and has a ratio of lactide to .epsilon.-caprolactone
residues from 60:40 to 90:10.
95. The pharmaceutical composition of claim 83, wherein the
biodegradable liquid polymer is formed with a hydroxy acid
initiator.
96. The pharmaceutical composition of claim 83, wherein the
biodegradable liquid polymer has a weight average molecular weight
of between about 1 kDa and about 35 kDa.
97. The pharmaceutical composition of claim 83, wherein the active
pharmaceutical ingredient makes up about 20 wt % of the
pharmaceutical composition, the biocompatible solvent or
combination or mixture of solvents and/or co-solvents makes up
about 50 wt % of the pharmaceutical composition, and the
biodegradable liquid polymer makes up about 30 wt % of the
pharmaceutical composition.
98. The pharmaceutical composition of claim 83, wherein the
pharmaceutical composition forms a liquid depot in a subject upon
injection and the liquid depot releases the active pharmaceutical
ingredient into the subject for a period of at least about 30
days.
99. A pharmaceutical composition, comprising: an active
pharmaceutical ingredient having a log P of at least about 0; a
biocompatible solvent or combination or mixture of solvents and/or
co-solvents; and a biodegradable liquid polymer comprising lactide
and .epsilon.-caprolactone residues and having a weight average
molecular weight of about 1 kDa-about 35 kDa, wherein a ratio of
lactide to .epsilon.-caprolactone residues is from 60:40-90:10,
wherein the active pharmaceutical ingredient is in substantially
solid form in the biodegradable liquid polymer and the
biocompatible solvent or combination or mixture of solvents and/or
co-solvents at body temperature, and wherein the active
pharmaceutical ingredient has a D.sub.v,50 of about 1 .mu.m-about
250 .mu.m and a particle size span of about 1-about 8.
100. The pharmaceutical composition of claim 99, wherein the active
pharmaceutical ingredient is a hydrophobic small molecule organic
compound or a pharmaceutically acceptable salt, ester, hydrate,
solvate, or prodrug thereof the active pharmaceutical and has a log
P of at least about 2.5.
101. The pharmaceutical composition of claim 99, wherein the
biocompatible solvent or combination or mixture of solvents and/or
co-solvents comprises a biocompatible solvent in combination with a
low-molecular weight (MW) polyethylene glycol (PEG).
102. A method of treating a subject, comprising injecting a
pharmaceutical composition into the body to the subject, wherein
the pharmaceutical composition comprises: an active pharmaceutical
ingredient having a log P of at least about 0; a biocompatible
solvent or combination or mixture of solvents and/or co-solvents;
and a biodegradable liquid polymer, wherein the active
pharmaceutical ingredient is in substantially solid form in the
biodegradable liquid polymer and the biocompatible solvent or
combination or mixture of solvents and/or co-solvents at body
temperature, wherein the active pharmaceutical ingredient has a
D.sub.v,50 of between about 1 .mu.m and about 250 .mu.m and a
particle size span of between about 1 and about 8, and wherein the
pharmaceutical composition forms a liquid depot in the body of the
subject upon injection and the liquid depot releases the active
pharmaceutical ingredient into the subject.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn. 119(e) to U.S. Provisional Patent Application
62/736,182, filed 25 Sep. 2018, the entirety of which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This application pertains to the field of biodegradable
liquid polymer compositions that are administered into the body
with syringes or needles and that are utilized to deliver a drug
into the body over an extended period of time.
BACKGROUND OF THE INVENTION
[0003] Biodegradable polymers are well known for their use in
biomedical applications, such as sutures, surgical clips, staples,
implants, and drug delivery systems. Such polymers include
polyglycolides, polylactides, polycaprolactones, polyanhydrides,
polyorthoesters, polydioxanones, polyacetals, polyesteramides,
polyamides, polyurethanes, polycarbonates, polyphosphazenes,
polyketals, polyhydroxybutyrates, polyhydroxyvalerates,
polyhyaluronic acid, and polyalkylene oxalates.
[0004] Initially, biodegradable polymers were solid materials that
were used to form solid articles such as sutures, staples, surgical
clips, implants or microcapsules and microparticles. Because the
polymers were solids, all of their applications in the biomedical
field required that the polymeric structures be formed outside the
body, and then inserted into the body for their use.
[0005] U.S. Pat. No. 5,278,201 to Dunn et al. (the "201 patent")
overcame the administration problems with the solid implants by
dissolving the solid biodegradable polymers in a biocompatible
solvent and injecting the solution into the body using standard
syringes and needles, where the polymer in the solution
precipitates or coagulates upon contact with aqueous body fluid to
form a solid implant matrix. However, there remained several
disadvantages with this in situ forming solid polymer system.
Because the polymers used had relatively high molecular weights,
the polymer solutions formed from the combination of the solid
polymers and the biocompatible solvents were quite viscous, and
administration required large bore needles and considerable
injection force, were not easily injected into muscle tissue, and
the solid implants formed from these polymer solutions tended to
cause local irritation of the muscular tissue. For this reason, the
foregoing polymer solutions were normally injected subcutaneously
where the material would form quite distinct and noticeable bumps.
Efforts by others to produce polymeric delivery systems that did
not include a solvent, or were formed using non-polymeric
materials, again suffered from viscosities unsuitable for
injection, or were not suitable for a variety of extended release
uses.
[0006] U.S. Pat. No. 8,187,640 to Dunn (the "640 patent") addressed
and solved problems associated with the solid implants of the '201
patent, by disclosing solution compositions of a biodegradable
liquid polymer combined with a biocompatible solvent, which solvent
would dissipate when the liquid polymer/solvent compositions were
placed in a body, thereby forming a viscous liquid polymer material
in the form of a film, a coating, a plug or other mass. The viscous
liquid polymer material does not solidify upon injection into the
body, but rather remains in situ in a viscous liquid form and, when
combined with a drug, provides both an initial burst and extended
release of the drug. The '640 patent disclosed that the rate of
release of a drug from the in situ viscous liquid material can be
controlled by altering the composition of the biodegradable
polymer. According to the '640 patent, the composition of the
liquid polymer, i.e., the type of monomer used or the ratio of
monomers for copolymers or terpolymers, the end groups on the
polymer chains, and the molecular weight of the polymer, determines
the hydrophilicity or lipophilicity of the polymer material, as
well as the degradation time of the liquid polymer implant. The
'640 patent disclosed that, for faster release rates and shorter
durations of release, more hydrophilic polymers can be used. For
slower release of drug and longer duration of release, more
hydrophobic polymer can be used. The '640 patent does not describe
suitable variations of the end groups of the polymer chains.
However, in the Examples section, this patent discloses the use of
an alcohol, dodecanol, as an initiator, which results in a hydroxy
group at the end of the polymer chain.
[0007] PCT Publication No. WO2017024027 describes the making of the
low viscosity liquid polymeric delivery system as disclosed in the
'640 patent to determine the rate and duration of release of drugs
following subcutaneous administration of the drug-loaded delivery
system. It was determined that the delivery system of the '640
patent is not suitable for long-term extended delivery of drugs
beyond, e.g., 14 days. PCT Publication No. WO2017024027 discloses a
different liquid polymer composition than that described in the
'640 patent, which provided a markedly improved extended release of
drugs as compared to the '640 patent. The liquid polymer
composition described in PCT Publication No. WO2017024027 included
a biodegradable liquid polymer with at least one carboxylic acid
end group, and a ratio of monomer units to carboxylic acid end
groups between about 5:1 and about 90:1.
[0008] Certain active pharmaceutical ingredients (APIs) have
relatively low solubility in aqueous media, and/or are relatively
hydrophobic (i.e. relatively low hydrophilicity). Such APIs may be
more difficult to solubilize and/or may remain in solid form (in
suspension) in various solvent systems as compared to APIs having
lesser hydrophobicity/greater hydrophilicity. The use of such APIs
in a liquid polymer composition can present special challenges in
that it is desirable to maintain a stable form of the API
throughout manufacturing, storage, and administration conditions,
which may involve exposure to a wide range of temperatures during
these processes. In addition, it would be desirable to be able
modify the components of a liquid polymer composition containing
such APIs in order to tailor the rate and duration of release of
the API from the composition according to a particular target
application. Therefore, there is a need in the art for liquid
polymer compositions for use with APIs having relatively low
solubility in aqueous media and/or relatively high hydrophobicity
(i.e., relatively low hydrophilicity), where such liquid polymer
compositions are stable over a wide range of temperatures and can
be modified to control release of the API in order to provide a
suitable extended release formulation for a target application.
SUMMARY OF THE INVENTION
[0009] It is one aspect of the present invention to provide a
pharmaceutical composition having an active pharmaceutical
ingredient in suspension, comprising an active pharmaceutical
ingredient having a log P of at least about 0; a biocompatible
solvent or combination or mixture of solvents and/or co-solvents;
and a biodegradable liquid polymer having a weight average
molecular weight between about 1 kDa and about 25 kDa, wherein the
active pharmaceutical ingredient is in substantially solid form in
the polymer and solvent or combination or mixture of solvents
and/or co-solvents at body temperature, and wherein the active
pharmaceutical ingredient has a D.sub.v,50 of between about 1 .mu.m
and about 250 .mu.m and a particle size span of between about 1 and
about 8.
[0010] It is another aspect of the present invention to provide a
pharmaceutical composition having an active pharmaceutical
ingredient in suspension, comprising an active pharmaceutical
ingredient having a log P of at least about 0; a biocompatible
solvent or combination or mixture of solvents and/or co-solvents;
and a biodegradable liquid polymer, wherein the active
pharmaceutical ingredient is substantially in solid form in the
polymer and solvent or combination or mixture of solvents and/or
co-solvents at temperatures up to between about body temperature
and at least about 45.degree. C.
[0011] It is another aspect of the present invention to provide a
pharmaceutical composition having an active pharmaceutical
ingredient in suspension, comprising an active pharmaceutical
ingredient having a log P of at least about 0; a biocompatible
solvent or combination or mixture of solvents and/or co-solvents;
and a biodegradable liquid polymer having a weight average
molecular weight between about 1 kDa and about 25 kDa, wherein the
active pharmaceutical ingredient has a D.sub.v,50 of between about
1 .mu.m and about 250 .mu.m and a particle size span of between
about 1 and about 8.
[0012] In embodiments, the active pharmaceutical ingredient may be
in substantially solid form in the polymer and solvent or
combination or mixture of solvents and/or co-solvents at
temperatures up to about 38.degree. C., or up to about 40.degree.
C.
[0013] In embodiments, the active pharmaceutical ingredient may be
in substantially solid form in the polymer and solvent or
combination or mixture of solvents and/or co-solvents at
temperatures up to at least about 45.degree. C.
[0014] In embodiments, the active pharmaceutical ingredient may be
in substantially solid form in the polymer and solvent or
combination or mixture of solvents and/or co-solvents at
temperatures between about 2.degree. C. and about 38.degree. C.
[0015] In embodiments, the active pharmaceutical ingredient may be
in substantially solid form in the polymer and solvent or
combination or mixture of solvents and/or co-solvents at
temperatures between about 2.degree. C. and about 45.degree. C.
[0016] In embodiments, the log P of the active pharmaceutical
ingredient may be at least about 2.5, or at least about 5.
[0017] In embodiments, prior to addition to the composition, the
active pharmaceutical ingredient may have a D.sub.v,50 of between
about 15 .mu.m and about 200 .mu.m and a particle size span of
between about 1 and about 8.
[0018] In embodiments, in the final composition, the active
pharmaceutical ingredient may have a D.sub.v,50 of between about 15
.mu.m and about 200 .mu.m and a particle size span of between about
1 and about 8.
[0019] In embodiments, prior to addition to the composition, or in
the final composition, the active pharmaceutical ingredient may
have a D.sub.v,50 of between about 15 .mu.m and about 150 .mu.m, or
between about 50 .mu.m and about 150 .mu.m, or between about 50
.mu.m and about 100 .mu.m, or between about 50 .mu.m and about 90
.mu.m, or between about 65 .mu.m and about 90 .mu.m.
[0020] In embodiments, the active pharmaceutical ingredient may
have a particle size span of between about 2 and about 6, or
between about 2 and about 5, or between about 2 and about 4.
[0021] In embodiments, the biocompatible solvent or combination or
mixture of solvents and/or co-solvents may be selected from the
group consisting of acetone, butyrolactone, .epsilon.-caprolactone,
N-cycylohexyl-2-pyrrolidone, diethylene glycol monomethyl ether,
dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide (DMSO),
ethyl acetate, ethyl lactate, N-ethyl-2-pyrrolidone, glycerol
formal, glycofurol, N-hydroxyethyl-2-pyrrolidone, isopropylidene
glycerol, lactic acid, methoxypolyethylene glycol, methoxypropylene
glycol, methyl acetate, methyl ethyl ketone, methyl lactate,
N-methyl-2-pyrrolidone (NMP), low-molecular weight (MW)
polyethylene glycol (PEG), polysorbate 80, polysorbate 60,
polysorbate 40, polysorbate 20, polyoxyl 35 hydrogenated castor
oil, polyoxyl 40 hydrogenated castor oil, sorbitan monolaurate,
sorbitan monostearate, sorbitan monooleate, benzyl alcohol,
n-propanol, isopropanol, tert-butanol, propylene glycol,
2-pyrrolidone, .alpha.-tocopherol, triacetin, tributyl citrate,
acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate,
esters thereof, and combinations and mixtures thereof.
[0022] In embodiments the biocompatible solvent or combination or
mixture of solvents and/or co-solvents comprises a biocompatible
solvent in combination with low-molecular weight (MW) polyethylene
glycol (PEG).
[0023] In embodiments, the biocompatible solvent or combination or
mixture of solvents and/or co-solvents may be selected from the
group consisting of: dimethyl sulfoxide (DMSO),
N-methyl-2-pyrrolidone (NMP), low-molecular weight (MW)
polyethylene glycol (PEG), and combinations and mixtures
thereof.
[0024] In embodiments, the biocompatible solvent or combination or
mixture of solvents and/or co-solvents may be selected from the
group consisting of: dimethyl sulfoxide (DMSO) in combination with
low-molecular weight (MW) polyethylene glycol (PEG), and
N-methyl-2-pyrrolidone (NMP) in combination with low-molecular
weight (MW) polyethylene glycol (PEG).
[0025] In embodiments, the biocompatible solvent or combination or
mixture of solvents and/or co-solvents may be
N-methyl-2-pyrrolidone (NMP) in combination with polyethylene
glycol (PEG) 300.
[0026] In embodiments, the biocompatible solvent or combination or
mixture of solvents and/or co-solvents may be dimethyl sulfoxide
(DMSO) in combination with polyethylene glycol (PEG) 400.
[0027] In embodiments, the active pharmaceutical ingredient may be
in a form selected from the group consisting of base form, esters,
hydrates, solvates, salts, and prodrugs.
[0028] In embodiments, the active pharmaceutical ingredient may be
in a crystalline form having a block-like crystal habit or a
needle-like crystal habit.
[0029] In embodiments, the active pharmaceutical ingredient may be
formed by at least one milling technique selected from the group
consisting of jet milling, nanomilling or wet milling in water or
other aqueous solvent followed by lyophilization or drying,
homogenization, ball milling, cutter milling, roller milling,
grinding with mortar and pestle, runner milling, and
cryomilling.
[0030] In embodiments, the biodegradable liquid polymer may
comprise lactide and .epsilon.-caprolactone residues.
[0031] In embodiments, the ratio of lactide to
.epsilon.-caprolactone residues may be from 60:40 to 90:10.
[0032] In embodiments, the ratio of lactide to
.epsilon.-caprolactone residues may be 75:25.
[0033] In embodiments, the biodegradable liquid polymer may be
formed with a hydroxy acid initiator.
[0034] In embodiments, the hydroxy acid initiator may be glycolic
acid.
[0035] In embodiments, the biodegradable liquid polymer may have a
weight average molecular weight between about 5 kDa and about 22
kDa.
[0036] In embodiments, the biodegradable liquid polymer may have a
weight average molecular weight between about 5 kDa and about 16
kDa.
[0037] In embodiments, the biodegradable liquid polymer may have a
weight average molecular weight between about 5 kDa and about 10
kDa.
[0038] In embodiments, the weight average molecular weight of the
biodegradble liquid polymer may be between about 10 kDa and about
16 kDa.
[0039] In embodiments, the weight average molecular weight of the
biodegradable liquid polymer may be between about 12 kDa and about
16 kDa.
[0040] In embodiments, the weight average molecular weight of the
biodegradable liquid polymer may be between about 1 kDa and about
10 kDa, between about 1 kDa and about 8 kDa, or between about 1 kDa
and about 5 kDa.
[0041] In embodiments, the composition may have a viscosity at room
temperature suitable for injection through a needle having a gauge
between about 16 and about 20.
[0042] In embodiments, the composition may have a shelf life of at
least about three months at a temperature selected from room
temperature and between 2.degree. C. and 8.degree. C.
[0043] In embodiments, the composition may form a liquid depot in a
subject upon injection, wherein the liquid depot releases the API
into the subject for a period of at least about 30 days.
[0044] In embodiments, the liquid depot may release the API into
the subject for a period of at least about 60 days.
[0045] In embodiments, the liquid depot may release the API into
the subject for a period of at least about 90 days.
[0046] In embodiments, the liquid depot may release the API into
the subject for a period of at least about 120 days.
[0047] In embodiments, the composition may further include an
additive, including, but not limited to, a surfactant. Examples of
surfactants suitable for use in the invention include, but are not
limited to, sucrose fatty acid esters.
[0048] It is another aspect of the present invention to provide a
pharmaceutical composition having an active pharmaceutical
ingredient in suspension, comprising an active pharmaceutical
ingredient, consisting of testosterone or a pharmaceutically
acceptable ester, hydrate, solvate, or prodrug thereof, or a salt
of any of said ester, hydrate, solvate or prodrug; a biocompatible
solvent system, consisting of approximately equal parts by weight
N-methyl-2-pyrrolidone (NMP) and polyethylene glycol having a
molecular weight of about 300 daltons (PEG 300); and an
acid-initiated biodegradable liquid polymer having a weight-average
molecular weight between about 1 kDa and about 25 kDa.
[0049] In embodiments, the biodegradable liquid polymer may be a
D,L-lactide/.epsilon.-caprolactone copolymer, wherein a ratio of
lactide monomer units to caprolactone monomer units in the
copolymer is about 75:25.
[0050] In embodiments, the active pharmaceutical ingredient may
make up about 20 wt % of the pharmaceutical composition, the
biocompatible solvent system may make up up about 50 wt % of the
pharmaceutical composition, and the biodegradable liquid polymer
may make up about 30 wt % of the pharmaceutical composition.
[0051] In embodiments, the active pharmaceutical ingredient may
have a D.sub.v,50 of between about 15 .mu.m and about 200 .mu.m and
a particle size span of between about 1 and about 8.
[0052] It is another aspect of the present invention to provide a
pharmaceutical composition, comprising about 20 wt % of
testosterone undecanoate having a D.sub.v,50 particle size of
between about 15 .mu.m and about 200 .mu.m; about 30 wt % of a
glycolic acid-initiated liquid 75:25
D,L-lactide/.epsilon.-caprolactone copolymer having a
weight-average molecular weight of between about 1 and about 25
kDa; between about 15 wt % and about 25 wt % of
N-methyl-2-pyrollidone (NMP); and between about 25 wt % and about
35 wt % of polyethylene glycol having a molecular weight of about
300 daltons (PEG 300), where the wt % of each of the NMP and PEG
300 total 50 wt % in the composition.
[0053] In embodiments, the pharmaceutical composition may comprise
about 15 wt % of the NMP and about 35 wt % of the PEG 300, wherein
the D.sub.v,50 particle size of the testosterone undecanoate is
between about 15 .mu.m and about 20 .mu.m, and the weight-average
molecular weight of the copolymer is about 10-16 kDa.
[0054] In embodiments, the pharmaceutical composition may comprise
about 25 wt % of the NMP and about 25 wt % of the PEG 300, wherein
the D.sub.v,50 particle size of the testosterone undecanoate is
between about 15 .mu.m and about 90 .mu.m, and the weight-average
molecular weight of the copolymer is about 10-16 kDa.
[0055] In embodiments, the pharmaceutical composition may comprise
about 25 wt % of the NMP and about 25 wt % of the PEG 300, wherein
the D.sub.v,50 particle size of the testosterone undecanoate is
between about about 35 .mu.m and about 90 .mu.m, and the
weight-average molecular weight of the copolymer is about 10-16
kDa.
[0056] In embodiments, the weight-average molecular weight of the
copolymer is between about 14 and 16 kDa.
[0057] In embodiments, the weight-average molecular weight of the
copolymer is between about 1 and 5 kDa, between about 1 and about
10 kDa, or between about 1 and about 12 kDa.
[0058] It is another aspect of the present invention to provide a
pharmaceutical composition, comprising about 15 wt % of
testosterone undecanoate; about 20 wt % of a glycolic
acid-initiated liquid 75:25 D,L-lactide/.epsilon.-caprolactone
copolymer having a weight-average molecular weight of between about
1 kDa and about 25 kDa; and about 65 wt % benzyl benzoate.
[0059] In embodiments, the weight-average molecular weight of the
copolymer may be between about 1 kDa and about 5 kDa, about 5 kDa,
about 8.5 kDa, about 10 kDa, about 12 kDa, about 14 kDa, about 14.2
kDa, about 15 kDa, about 15.5 kDa, or about 22 kDa.
[0060] In embodiments, the active pharmaceutical ingredient may
have a particle size span of between about 1 and about 8.
[0061] It is another aspect of the present invention to provide a
pharmaceutical composition for use as a medicament or in the
treatment of a disease, comprising an active pharmaceutical
ingredient having a log P of at least about 0; a biocompatible
solvent or combination or mixture of solvents and/or co-solvents;
and a biodegradable liquid polymer, wherein at least one of the
following is true: the biodegradable liquid polymer has a weight
average molecular weight of between about 1 kDa and about 25 kDa;
the active pharmaceutical ingredient is in substantially solid form
in the biocompatible solvent or combination or mixture of solvents
and/or co-solvents at body temperature; and the active
pharmaceutical ingredient has a D.sub.v,50 of between about 1 .mu.m
and about 250 .mu.m and a particle size span of between about 1 and
about 8.
[0062] It is another aspect of the present invention to provide a
method of testosterone supplementation in a subject, comprising
administering to the subject a pharmaceutical composition of the
invention, wherein the active pharmaceutical ingredient comprises
at least one of testosterone, an ester, complex, hydrate, solvate,
or prodrug of testosterone, and a salt of any of said esters,
complexes, hydrates, solvates, and prodrugs.
[0063] In embodiments, a serum testosterone level of the subject
may be between about 3 ng/mL and about 10 ng/mL for at least about
one month after the administering step.
[0064] In embodiments, a serum testosterone level of the subject
may be between about 3 ng/mL and about 10 ng/mL for at least about
two months after the administering step.
[0065] In embodiments, a serum testosterone level of the subject
may be between about 3 ng/mL and about 10 ng/mL for at least about
three months after the administering step.
[0066] It is another aspect of the present invention to provide a
method of treating a subject, comprising administering to the
subject a pharmaceutical composition of the invention.
[0067] In embodiments, the active pharmaceutical ingredient of the
pharmaceutical composition may be testosterone undecanoate.
[0068] In embodiments, the active pharmaceutical ingredient of the
pharmaceutical composition may be testosterone cypionate.
[0069] In embodiments, a pharmaceutical composition of the
invention is administered subcutaneously to a subject.
[0070] It is another aspect of the present invention to provide a
malleable, non-rigid, non-solid implant formed upon administration
of a pharmaceutical composition of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0071] FIGS. 1A and 1B show the testosterone undecanoate release
rate (mg/day), and the percentage testosterone undecanoate (TU)
released over time, respectively, for four Liquid Polymer
Technology (LPT)-TU formulations of the invention in an in vitro
release assay (LPT-TU Test Formulations 1 (.box-solid.), 2
(.tangle-solidup.) and 3 (.smallcircle.), and Control LPT
Formulation (X).
[0072] FIG. 1C shows the temperature at which the suspended drug in
the three LPT-TU formulations from Table 3 becomes fully dissolved
and the formulation forms a solution.
[0073] FIG. 2 shows the results of an in vivo experiment comparing
the mean testosterone concentration (ng/mL) in rats after injection
with various LPT-TU Test Formulations of the invention (LPT-TU Test
Formulations 1 (.zeta.), 2 (.tangle-solidup.) and 3
(.smallcircle.), and Non-Polymeric TU Control Solution
(.quadrature.)).
[0074] FIGS. 3A and 3B show the in vitro TU release rate (mg/day)
and percentage testosterone undecanoate (TU) released over time,
respectively, for four LPT-TU formulations comprising polymer
having a weight average molecular weight of approximately 10 kDa,
where the TU particle size and amount of co-solvent in the
formulation were varied (LPT-TU Test Formulations 4 (.box-solid.);
Test Formulation 5 (.tangle-solidup.); Test Formulation 6
(.circle-solid.); Test Formulation 7 (.diamond-solid.)).
[0075] FIGS. 3C and 3D show the in vitro TU release rate (mg/day)
and percentage testosterone undecanoate (TU) released over time,
respectively, for four LPT-TU formulations comprising polymer
having a weight average molecular weight of approximately 14 kDa,
where the TU particle size and amount of co-solvent in the
formulation were varied (LPT-TU Test Formulations 8 (.box-solid.);
Test Formulation 9 (.smallcircle.); Test Formulation 10
(.diamond.); Test Formulation 11 (.DELTA.)).
[0076] FIGS. 3E and 3F show the in vitro TU release rate (mg/day)
and percentage testosterone undecanoate (TU) released over time,
respectively, for four LPT-TU formulations comprising polymer
having a weight average molecular weight of approximately 22 kDa,
where the TU particle size and amount of co-solvent in the
formulation were varied (LPT-TU Test Formulations 12 (--X--); Test
Formulation 13 (--+--); Test Formulation 14 (); Test Formulation 15
(--.quadrature.--)).
[0077] FIGS. 4A and 4B show the in vitro TU release rate (mg/day)
and percentage testosterone undecanoate (TU) released over time,
respectively, for four LPT-TU formulations comprising TU having a
D.sub.v,50 particle size of approximately 15 .mu.m, where the
weight average molecular weight of the polymer and the amount of
co-solvent in the formulation were varied (LPT-TU Test Formulations
4 (.box-solid.); Test Formulation 7 (.diamond-solid.); Test
Formulation 8 (.quadrature.); Test Formulation 12 (--X--); and Test
Formulation 14 ().
[0078] FIGS. 4C and 4D show the in vitro TU release rate (mg/day)
and percentage testosterone undecanoate (TU) released over time,
respectively, for four LPT-TU formulations comprising TU having a
D.sub.v,50 particle size of approximately 56 .mu.m, where the
weight average molecular weight of the polymer and the amount of
co-solvent in the formulation were varied (LPT-TU Test Formulations
6 (.circle-solid.); Test Formulation 9 (.smallcircle.); and Test
Formulation 10 (.diamond.)).
[0079] FIGS. 4E and 4F show the in vitro TU release rate (mg/day)
and percentage testosterone undecanoate (TU) released over time,
respectively, for four LPT-TU formulations comprising TU having a
D.sub.v,50 particle size of approximately 64 .mu.m or 90 .mu.m,
where the weight average molecular weight of the polymer and the
amount of co-solvent in the formulation were varied (LPT-TU Test
Formulations 5 (.tangle-solidup.); Test Formulation 11 (.DELTA.);
Test Formulation 13 (--+--); and Test Formulation 15
(--.quadrature.--)).
[0080] FIG. 4G shows the temperature at which the suspended drug in
eleven of the LPT-TU formulations from Table 4 becomes fully
dissolved and the formulation forms a solution.
[0081] FIGS. 5A and 5B show the in vitro TU release rate (mg/day)
and percentage testosterone undecanoate (TU) released over time,
respectively, for five LPT-TU formulations comprising the same
polymer and solvent system, but where the D.sub.v,50 particle size
of the TU in the formulation was varied (Test Formulation 16 (6
.mu.m TU; .quadrature.), Test Formulation 17 (15 .mu.m TU;
.diamond.), Test Formulation 18 (56 .mu.m TU; .smallcircle.), Test
Formulation 19 (64 .mu.m TU; X), and Test Formulation 20 (86 .mu.m
TU; .diamond-solid.).
[0082] FIGS. 5C and 5D show the in vitro TU release rate (mg/day)
and percentage testosterone undecanoate (TU) released over time,
respectively, for five LPT-TU formulations comprising the same
polymer and solvent system, but where the particle size
distribution of the TU in the formulation was varied (6 .mu.m TU
(100%), .circle-solid.); 64 .mu.m/6 .mu.m (60%/40%), .DELTA.; 64
.mu.m/6 .mu.m (80%/20%), .diamond.; and 64 .mu.m (100%),
.box-solid.).
[0083] FIGS. 6A and 6B show the in vitro TU release rate (mg/day)
and percentage testosterone undecanoate (TU) released over time,
respectively, for four different LPT-TU formulations of the
invention (Test Formulation 2 (.circle-solid.); Test Formulation 21
(.quadrature.), Test Formulation 22 (.tangle-solidup.) and Test
Formulation 23 (.diamond.)).
[0084] FIG. 7 shows the results of an in vivo experiment comparing
the mean testosterone concentration (ng/mL) in rats after injection
with various LPT-TU Test Formulations of the invention (Test
Formulation 21(.circle-solid.), Test Formulation 22 (X), and Test
Formulation 23 (.DELTA.); Non-Polymeric TU Control Solution
(.quadrature.).
[0085] FIG. 8 shows the results of an in vivo experiment comparing
the mean testosterone concentration (ng/mL) in minipigs after
injection with various LPT-TU Test Formulations of the invention
(Test Formulation 22 (X) and Test Formulation 23 (.DELTA.)).
[0086] FIG. 9 shows the results of an in vivo experiment comparing
the mean testosterone concentration (ng/mL) in minipigs after
injection with various LPT-TU Test Formulations of the invention
(Non-Polymeric TU Control Solution Group A one dose (.quadrature.);
Non-Polymeric TU Control Solution Group A two doses (X); Test
Formulation Group C (.star-solid.); Test Formulation Group D ( );
Test Formulation Group E (.diamond.); Test Formulation Group
F()).
[0087] FIGS. 10A and 10B show the in vitro TU release rate (mg/day)
and percentage testosterone undecanoate (TU) released over time,
respectively, for five LPT-TU formulations in which the TU is in
solution in the formulation, as compared to an LPT-TU suspension
control (Test Formulation A (.quadrature.); Test Formulation B
(.smallcircle.); Test Formulation C (.DELTA.); Test Formulation D
(.diamond-solid.); Test Formulation E (.box-solid.) and Control
Suspension (.circle-solid.)).
[0088] FIG. 11 shows the results of an in vivo experiment comparing
the mean testosterone concentration (ng/mL) in rats after injection
with an LPT-TU Solution Test Formulation of the invention (Test
Formulation A (), Non-Polymeric TU Control Solution
(.quadrature.)).
[0089] FIG. 12 shows the results of an in vivo experiment comparing
the mean testosterone concentration (ng/mL) in rats after injection
with various LPT-TU Solution and Suspension Test Formulations of
the invention (Test Formulation C (.diamond-solid.); Test
Formulation D ( ); Test Formulation 2 (.tangle-solidup.); and
Non-Polymeric TU Control Solution (.quadrature.)).
[0090] FIG. 13 shows the temperature at which the suspended drug in
six of the LPT-TC formulations of the invention becomes fully
dissolved and the formulation forms a solution.
[0091] FIGS. 14A and 14B show the testosterone cypionate (TC)
release rate (mg/day), and the percentage TC released over time,
respectively, for three LPT-TC formulations of the invention in an
in vitro release assay (LPT-TC Test Formulations 1
(.diamond-solid.), 2 (.tangle-solidup.), and 4 (.box-solid.)).
DETAILED DESCRIPTION OF THE INVENTION
[0092] Certain active pharmaceutical ingredients (APIs) have
relatively low solubility in aqueous media and/or relatively high
hydrophobicity (i.e., relatively low hydrophilicity). Such APIs may
be more difficult to solubilize in pharmaceutically acceptable
solvent systems and/or may be more likely to remain in solid form,
i.e. in suspension, in such solvent systems as compared to APIs
having higher aqueous solubility and/or lower hydrophobicity (i.e.,
higher hydrophilicity). Such APIs are also less likely to dissolve
in biological fluids (e.g., plasma, gastric juices) and may thus
have lower bioavailability, especially when provided in certain
dosage forms, including oral dosage forms and parenteral dosage
forms, and it can be especially difficult to formulate compositions
of these APIs that allow for extended release of the drug.
[0093] The present invention provides pharmaceutical compositions
of hydrophobic and/or poorly water-soluble APIs that are suitable
for, among other uses, extended release of the API upon
administration to a patient. The present invention achieves this
and other benefits by the creation of stable suspensions of the
API, or alternatively stable solutions of the API, in an extended
release form, which the present invention accomplishes by the
inclusion of a liquid polymer/solvent system in the pharmaceutical
formulation, to form a "liquid polymer composition" or "liquid
polymer formulation" (also referred to herein as a Liquid Polymer
Technology (LPT) composition or formulation). When pharmaceutical
compositions (formulations) are provided using the liquid
polymer/solvent system of the invention and using the guidance
provided herein, the API that is in solid form (suspension) in such
a formulation advantageously remains in a stable physical form
(e.g., the API does not undergo a phase change, or remains in
substantially solid or suspension form) at room temperature (i.e.,
during manufacture, transportation, and/or storage) and at body
temperature (i.e., in vivo within the body of the patient and when
exposed to the internal environment of the body of the patient). In
some embodiments of the invention, the API which is in suspension
in the formulation also remains in a stable physical form within
the inventive formulations at temperatures higher than body
temperature, such as temperatures that may be experienced during
terminal sterilization processes, including electron beam (e-beam)
irradiation. In some embodiments of the invention, the API is in a
solution form in the formulation (i.e., is substantially or fully
dissolved in the formulation), as described in more detail below.
The formulations of the invention in which the API is in solution
form are also stable (i.e., the API does not undergo phase changes,
such as by precipitating in the formulation) over a large range of
temperatures. In other words, liquid polymer compositions of the
invention that provide the API in suspension are stable in that the
API does not readily dissolve in the formulation, and liquid
polymer compositions of the invention that provide the API in
solution are stable in that the API does not readily precipitate in
the formulation.
[0094] Pharmaceutical liquid polymer compositions of the invention
are also characterized in that they remain substantially stable at
cold storage temperatures (e.g., refrigeration temperatures),
meaning that the compositions do not freeze and/or do not show an
unacceptable degree of degradation when stored at these
temperatures over a reasonable extended period of time.
[0095] Moreover, the liquid polymer compositions of the invention
remain in liquid form in vivo, i.e., liquid polymer compositions of
the invention do not form a solid implant in vivo, even after the
solvent has dissipated from the polymer upon exposure to the
aqueous environment in the body.
[0096] Without wishing to be bound by any particular theory, it is
believed that the liquid polymer pharmaceutical compositions of the
present invention are stable at temperatures ranging from cold
storage temperatures (or lower), up to room temperature, or up to
in vivo temperatures, or even up to higher temperatures as a result
of a combination of factors. Such factors include at least the
chosen solvent or solvent system and the molecular weight and
composition of the liquid polymer. Liquid polymer pharmaceutical
compositions of the present invention are also suitable for use as
extended release formulations as a result of a combination of
factors, including at least the chosen solvent or solvent system
and the molecular weight and composition of the liquid polymer, and
the particle size of the API (when the formulation provides the API
in suspension). One or more of these factors may affect one or more
of the other factors; by way of non-limiting example, certain
solvents or solvent systems affect the stability of the liquid
polymer, particularly at a given temperature (e.g., refrigeration
temperatures), and thus affect the stability of the pharmaceutical
composition as a whole. Similarly, certain solvents or solvent
systems affect the stability of the physical form of the API when
provided within the liquid polymer formulation throughout a large
range of temperatures, including temperatures experienced in an in
vivo environment.
[0097] Accordingly, the present invention is directed to
biodegradable liquid polymer technology (LPT) pharmaceutical
compositions that can be administered into the body with syringes
or needles and that are utilized to deliver a drug (active
pharmaceutical ingredient, or API) into the body over an extended
period of time. Such compositions can deliver APIs to a patient at
consistent levels within a therapeutic window for long periods of
time to allow for improved ease of administration, resulting in
improved patient compliance with administration protocols. In
particular, the present invention is directed to LPT pharmaceutical
compositions, also referred to as LPT formulations, which include a
biodegradable polymer, a solvent or combination or mixture of
solvents and/or co-solvents, and an active pharmaceutical
ingredient (API) that is characterized as having relatively low
solubility in aqueous media and/or relatively high hydrophobicity
(i.e. relatively low hydrophilicity). The LPT formulations of the
invention remain liquid after administration to the body (e.g., the
formulations do not form solid implants, as discussed in detail
herein), and LPT formulations remain stable with respect to both
the polymer and the API over a wide range of temperatures.
[0098] By way of illustrating the present invention, during
development of an LPT formulation for the delivery of an API having
relatively low solubility in aqueous solutions, namely testosterone
undecanoate (TU), an LPT-TU formulation was designed to incorporate
the API in substantially solid form (i.e., as a suspension). The
LPT-TU formulation was comprised of 20 wt % TU, 30 wt % LPT polymer
(75:25 DL-lactide/.epsilon.-caprolactone liquid copolymer), and 50
wt % N-methyl-2-pyrrolidone (NMP). This formulation provided an
injectable extended release formulation for the delivery of
testosterone prodrug (in this case, TU) in the form of an oil-free
formulation, which eliminated or reduced the risk of pulmonary oil
microembolism (a risk associated with one of the current commercial
injectable products for the delivery of TU). However, it was
unexpectedly discovered that when the formulation was terminally
sterilized using e-beam irradiation, which is one method used to
terminally sterilize a product prior to injection, sample
temperatures increased to -35-40.degree. C., and the suspended TU
dissolved into the polymer matrix. As the samples cooled, TU
crystallized in an uncontrolled fashion. This led to unacceptable
variability in the TU particle size, which affected injectability
of the formulation.
[0099] Therefore, a TU recrystallization method was developed, and
implemented after e-beam irradiation. This allowed for control of
TU particle size within the formulation, which in turn provided for
acceptable injectability with the target needle gauge. However, the
recrystallized LPT-TU formulation surprisingly had a decreased
degradation rate, altered degradation mode, exhibited less
desirable in vitro release kinetics, and exhibited slow in vivo
release that did not maintain testosterone levels within the
targeted therapeutic range.
[0100] To address these issues, the inventors designed and
developed new liquid polymer formulations suitable for use with TU
(which are expected also be useful for APIs similar to TU, such as
APIs that have relatively low solubility in aqueous environments
and highly variable solubility in organic solvents, dependent on
the characteristics of the solvent). These formulations were
designed to be suitable for use in a clinical product and with the
desired manufacturing processes for such products, including
desired sterilization processes. The new formulations were designed
to have most or all of the following characteristics, using TU as
an API that is exemplary of the present invention: [0101] Comprised
of a biocompatible solvent (or solvent and co-solvent),
biodegradable liquid polymer, and API, with other additives being
acceptable if necessary and safe for injection (e.g., by parenteral
injection, including, but not limited to subcutaneous or
intramuscular injection); [0102] Exists as either a solution, or a
suspension with controlled particle size; [0103] Has a viscosity
sufficiently low to facilitate resuspension (if necessary) and
injection; [0104] API within the formulation should not undergo
phase transitions within the temperature range of refrigeration
temperatures (about 2-8.degree. C.) up to at least body
temperatures (about 36.5.degree. C. to about 37.5.degree. C.),
and/or up to at least 40-45.degree. C. or higher; [0105] Compatible
with terminal sterilization processes (e.g., electron beam (e-beam)
irradiation, gamma irradiation, X-ray irradiation); [0106] Can be
delivered via subcutaneous injection using a small gauge needle
(>20 G); [0107] Forms a non-solid, soft implant which ideally
does not impact physical mobility when injected into the body;
[0108] Meets stability requirements as either a room temperature or
refrigerated product for .gtoreq.2 years; [0109] Specifically for
TU and related drugs (e.g., testosterone cypionate), provides
testosterone supplementation in the eugonadal range (10.4-34.7
nmol/L or 3-10 ng/mL testosterone in plasma (see, e.g., Shehzad
Basaria, "Male hypogonadism," 383 Lancet 1250 (2014) (hereinafter
"Basaria"); Abraham Morgentaler et al., "Long acting testosterone
undecanoate therapy in men with hypogonadism: results of a
pharmacokinetic clinical study," 180 J. Urology 2307 (2008)
(hereinafter "Morgentaler")): [0110] .gtoreq.75% patients have
total testosterone C.sub.avg from 3-10 ng/mL; [0111] The lower
limit of the 95% CI for percent of subjects with C.sub.avg within
the eugonadal range is >65%; [0112] Specifically for TU and
related drugs (e.g., testosterone cypionate), has acceptable
C.sub.max, per USFDA thresholds (e.g., see Morgentaler et al.,
supra); [0113] No instances of C.sub.max.gtoreq.25 ng/mL; [0114]
.sigma.<5% C.sub.max between 18 and 25 ng/mL; [0115] .gtoreq.85%
C.sub.max.ltoreq.15 ng/mL; and [0116] Specifically for TU and
related drugs (e.g., testosterone cypionate), provides testosterone
supplementation for at least 8, 9 or 10 weeks, and in some
embodiments, at least 11 or 12 weeks, and in some embodiments,
greater than 12 weeks.
[0117] Multiple new LPT formulations were designed utilizing a
variety of: LPT copolymers and polymer ratios, polymer molecular
weights, solvents and solvent combinations, additives, drug
processing steps (for suspensions), and drug/polymer/solvent
ratios. In particular, the inventors designed LPT formulations with
the goals of: (1) increasing drug release and depot degradation in
vivo, while maintaining the extended release capability of the
formulations; (2) forming LPT solution formulations that were
stable within target temperature ranges and time periods; and (3)
forming LPT suspension formulations that were stable within target
temperature ranges and time periods. These LPT formulations were
then evaluated for characteristics including:
viscosity/injectability, drug (e.g., TU or TC) solubility in the
formulation, liquid depot degradation rate, polymer stability, in
vitro drug (e.g., TU or TC) release, formulation freeze
temperatures (to evaluate phase stability at refrigeration
temperatures), and drug (e.g., TU or TC) dissolution temperatures,
e.g., temperatures where drug in suspension in the formulation
dissolves and the formulation becomes a solution (to evaluate phase
stability at higher temperatures, such as those experienced during
e-beam irradiation).
Definitions
[0118] As used herein, the term "animal" refers to any organism of
the kingdom Animalia. Examples of "animals" as that term is used
herein include, but are not limited to, humans (Homo sapiens);
companion animals, such as dogs, cats, and horses; and livestock
animals, such as cows, goats, sheep, and pigs.
[0119] As used herein, the term "biocompatible" means "not harmful
to living tissue."
[0120] As used herein, the term "biodegradable" refers to any
water-insoluble material that is converted under physiological
conditions into one or more water-soluble materials, without regard
to any specific degradation mechanism or process.
[0121] As used herein, the term "co-solvent" refers to a substance
added to a solvent to increase or modify the solubility of a solute
in the solvent.
[0122] As used herein, the term "liquid" refers to the ability of a
composition to undergo deformation under a shearing stress,
regardless of the presence or absence of a non-aqueous solvent.
Liquid polymer compositions and the liquid polymers (also referred
to as "liquid polymers) according to the invention have a liquid
physical state at ambient and body temperatures and remain liquid
in vivo, i.e., in a largely aqueous environment. The liquid polymer
compositions and liquid polymers have a definite volume, but are an
amorphous, non-crystalline mass with no definite shape. In
addition, the liquid polymers according to the invention are not
soluble in body fluid or water and therefore, after injection into
the body and dissipation of the solvent, remain as a cohesive mass
when injected into the body without themselves significantly
dissipating. In addition, such liquid polymer compositions can have
a viscosity, density, and flowability to allow delivery of the
composition through standard gauge or small gauge needles (e.g.,
18-26 gauge) with low to moderate injection force using standard
syringes. The liquid polymers of the present invention are further
characterized as not forming a solid implant in situ in the body
when injected into the body as part of a sustained release drug
delivery system that includes the liquid polymers and a
biocompatible solvent. In other words, liquid polymers according to
the present invention remain in a substantially liquid form in situ
upon exposure to an aqueous environment, such as upon injection
into the body, including after the solvent in the administered
composition has dissipated. The liquid polymers of the present
invention can be further characterized being non-crystalline,
amorphous, non-thermoplastic, non-thermosetting, and/or non-solid.
"Liquids," as that term is used herein, may also exhibit
viscoelastic behavior, i.e. both viscous and elastic
characteristics when undergoing deformation, such as time-dependent
and/or hysteretic strain. By way of non-limiting example,
viscoelastic materials that are generally flowable but have a
partially solid character and/or a plastic- or gel-like character,
such as cake batter or raw pizza dough, and similar materials, are
"liquids" as that term is used herein. In some embodiments,
materials having a non-zero yield stress that do not deform at
stresses below the yield stress, and that are readily deformable
without a characteristic of material fracture or rupture at
materials above the yield stress, may be "liquids" as that term is
used herein.
[0123] As used herein, the terms "molecular weight" and "average
molecular weight," unless otherwise specified, mean a
weight-average molecular weight as measured by a conventional gel
permeation chromatography (GPC) instrument (such as an Agilent 1260
Infinity Quaternary LC with Agilent G1362A Refractive Index
Detector) utilizing polystyrene standards and tetrahydrofuran (THF)
as the solvent.
[0124] As used herein, the terms "patient" and "subject" are
interchangeable and refer generally to an animal to which a
composition or formulation of the invention is administered or is
to be administered.
[0125] As used herein, the term "polymer" refers generally to
polymers, copolymers and/or terpolymers formed of repeating units,
which can be linear, branched, grafted and/or star-shaped.
Non-limiting examples of polymers include polyglycolides,
polylactides, polycaprolactones, polyanhydrides, polyorthoesters,
polydioxanones, polyacetals, polyesteramides, polyamides,
polyurethanes, polycarbonates, polyphosphazenes, polyketals,
polyhydroxybutyrates, polyhydroxyvalerates, polyethylene glycols,
polyesters, and polyalkylene oxalates. Water-insoluble polymers
that are converted under physiological conditions into one or more
water-soluble materials are referred to as herein as "biodegradable
polymers," and non-limiting examples of biodegradable polymers
include co-polymers or terpolymers comprising: lactide monomers and
caprolactone monomers, lactide monomers and trimethylene carbonate
monomers, or lactide monomers and dioxanone monomers.
[0126] As used herein, the term "small molecule" means an organic
compound having a molecular weight less than 900 daltons.
[0127] As used herein, the term "solvent" refers to a liquid that
dissolves a solid or liquid solute, or to a liquid external phase
of a suspension throughout which solid particles are dispersed.
[0128] As used herein, the term "solubilizer" refers to a compound
that increases the solubility of another substance. Examples of
solubilizers useful in the present invention include any
solubilizer useful for parenteral injection, and include, but are
not limited to, surfactants and other solubilizers, such as
Poloxamer 188, sorbitan trioleate, lecithin (e.g., soya or egg),
Vitamin E TPGS, sugar based esters or ethers (e.g., sugar acid
esters of fatty alcohols or sugar alcohol esters of fatty acids,
including, but not limited to, sucrose cocoate, sucrose stearate,
sucrose laurate, etc,), amino acid-based solubility enhancers
(e.g., proline, arginine, DL-methionine), and protein-based
solubility enhancers (e.g., hydrophobins).
[0129] As used herein, the term "surfactant" refers to a compound
that lowers the surface tension between two liquids, between a gas
and a liquid, or between a liquid and a solid. For example, a
surfactant can act as a wetting agent, which aids in dispersing an
active pharmaceutical ingredient in a liquid vehicle, or as a
solubilizer.
[0130] As used herein, the term "sucrose fatty acid ester" or
"sucrose ester" or "sugar ester" or "sucrose fatty acid ether" or
"sucrose ether" or "sugar ether" refers to a group of surfactants
chemically synthesized from esterification or etherification,
respectively, of a sugar, sugar alcohol, or sugar derivative (e.g,
sucrose or other sugar) and fatty acids (or glycerides) or fatty
alcohols. Because they have amphiphilic properties, they have the
ability to bind to both water and oil simultaneously and are thus
useful as emulsifiers or stabilizers.
[0131] Unless otherwise specified, all ratios between monomers in a
copolymer disclosed herein are molar ratios.
[0132] Unless otherwise specified, all particle sizes and particle
size distributions disclosed herein are determined according to
volume-based particle size measurements, such as, by way of
non-limiting example, by use of a laser diffraction particle size
analyzer such as a Malvern Mastersizer.RTM. instrument. Software
programs and calculations that can convert from a number-based
distribution analysis to a volume-based distribution analysis (and
vice versa) are well known in the art; therefore, for particle
sizes calculated using a number-based method, a volume-based
particle size can also be estimated. Volume-based particle size
distribution measurements are the default choice for many ensemble
light scattering particle size measurement techniques, including
laser diffraction, and are generally used in the pharmaceutical
industry.
[0133] One embodiment of the invention is a pharmaceutical
composition having an active pharmaceutical ingredient (API) in
suspension where the API is characterized as having relatively low
solubility in aqueous media and/or relatively high hydrophobicity
(i.e. relatively low hydrophilicity). The formulation includes such
an API (e.g., an API having an octanol-water partition coefficient
of at least about 1), a biocompatible solvent or combination or
mixture of solvents and/or co-solvents, and a biodegradable liquid
polymer having a molecular weight between about 1 kDa and about 25
kDa. The API is substantially in solid form (in suspension) in the
liquid polymer and solvent(s) and the API does not undergo phase
transition (e.g., does not substantially dissolve in the
formulation, remains in suspension, or remains in substantially
solid form) in the liquid polymer and solvent(s) at temperatures up
to at least body temperature (e.g., about 36.5.degree. C. to about
37.5.degree. C. (about 97.7.degree. F. to about 99.5.degree. F.)).
In one embodiment, the API is in substantially solid form in the
liquid polymer and solvent(s) up to temperatures that are higher
than body temperatures, such as temperatures up to 40-45.degree. C.
In one embodiment, the API remains substantially in solid form (the
API does not undergo a phase transition) in the liquid polymer and
solvent(s) up to at least 45.degree. C. or higher. In one
embodiment, the liquid polymer composition (i.e., the composition
including the liquid polymer, solvent(s) and API) does not undergo
a phase transition (e.g., does not freeze) at refrigeration
temperatures e.g., between about 2.degree. C. and 8.degree. C. In
one embodiment, the active pharmaceutical ingredient has a
volume-based particle size distribution median (D.sub.v,50) of
between about 15 .mu.m and about 200 .mu.m and a particle size span
of between about 1 and about 8. In one embodiment, and by way of
example, the API has an octanol-water partition coefficient of at
least about 1. In one embodiment, such an API has a log P of
greater than 0. In one embodiment, such an API has a log P of
greater than about 5.
[0134] Another embodiment of the invention is a pharmaceutical
composition having an active pharmaceutical ingredient (API) in
solution where the API is characterized as having relatively low
solubility in aqueous media and/or relatively high hydrophobicity
(i.e. relatively low hydrophilicity). The formulation includes such
an API (e.g., an API having an octanol-water partition coefficient
of at least about 1), a biodegradable liquid polymer having a
molecular weight between about 1 kDa and about 25 kDa, and a
biocompatible solvent or combination or mixture of solvents and/or
co-solvents, where the API is substantially or fully dissolved (in
solution) in the polymer/solvent formulation. In this embodiment,
the API does not undergo phase transition (e.g., does not come out
of solution) in the composition when exposed to a variety of
temperatures, e.g., temperatures ranging from about 2.degree. C. or
lower to at about 38.degree. C. or higher.
Active Pharmaceutical Ingredient (API)
[0135] APIs suitable for use in embodiments of the present
invention generally include drugs having low solubility in aqueous
media and/or relatively high hydrophobicity (i.e., relatively low
hydrophilicity), and which thus are more difficult to solubilize in
pharmaceutically acceptable solvent systems and/or may be more
likely to remain in solid form, i.e., in suspension, in such
polymer/solvent systems as compared to APIs having higher aqueous
solubility and/or lower hydrophobicity (i.e. higher
hydrophilicity). Hydrophobic and/or poorly water-soluble APIs that
are intended to be released and/or administered to a patient over a
period of multiple weeks or months may be especially desirable for
use in the present invention, given the difficulty of formulating
extended release compositions of these APIs by the methods and
systems of the prior art.
[0136] Low solubility in aqueous media can be determined by
different methods known to those in the art and in some
embodiments, will include APIs having an octanol-water partition
coefficient (P) of at least about 1, i.e. a log(P) of at least
about 0, and such APIs may often have a P of at least about
100,000, i.e. a log(P) of at least about 5. Thus, the log(P) of
APIs used in the present invention may be at least about 0, at
least about 1, at least about 2, at least about 3, at least about
4, at least about 5, at least about 6, at least about 7, or at
least about 8, or in other embodiments at least about any tenth of
an integer between 0 and 8, i.e. at least about 0, at least about
0.1, at least about 0.2, at least about 0.3, at least about 0.4, at
least about 0.5, at least about 0.6, at least about 0.7, at least
about 0.8, at least about 0.9, at least about 1, at least about
1.1, at least about 1.2, at least about 1.3, at least about 1.4, at
least about 1.5, at least about 1.6, at least about 1.7, at least
about 1.8, at least about 1.9, at least about 2, at least about
2.1, at least about 2.2, at least about 2.3, at least about 2.4, at
least about 2.5, at least about 2.6, at least about 2.7, at least
about 2.8, at least about 2.9, at least about 3, at least about
3.1, at least about 3.2, at least about 3.3, at least about 3.4, at
least about 3.5, at least about 3.6, at least about 3.7, at least
about 3.8, at least about 3.9, at least about 4, at least about
4.1, at least about 4.2, at least about 4.3, at least about 4.4, at
least about 4.5, at least about 4.6, at least about 4.7, at least
about 4.8, at least about 4.9, at least about 5, at least about
5.1, at least about 5.2, at least about 5.3, at least about 5.4, at
least about 5.5, at least about 5.6, at least about 5.7, at least
about 5.8, at least about 5.9, at least about 6, at least about
6.1, at least about 6.2, at least about 6.3, at least about 6.4, at
least about 6.5, at least about 6.6, at least about 6.7, at least
about 6.8, at least about 6.9, at least about 7, at least about
7.1, at least about 7.2, at least about 7.3, at least about 7.4, at
least about 7.5, at least about 7.6, at least about 7.7, at least
about 7.8, at least about 7.9, or at least about 8.
[0137] A partition coefficient (e.g., octanol-water partition
coefficient, using e.g., 1-octanol) is a measure of the relative
hydrophobicity and hydrophilicity of a compound, and more
particularly, a partition coefficient describes the propensity of a
neutral (uncharged) compound to dissolve in an immiscible biphasic
system of lipid (fats, oils, organic solvents) and water. In simple
terms, it measures how much of a solute dissolves in the water
portion versus an organic portion. When log(P) is zero, the
compound is equally partitioned (equally soluble) between lipid and
aqueous phases; when the log(P) is greater than 0, the compound is
more lipophilic (or hydrophobic), meaning that the compound is more
soluble in a lipid phase, and when the log(P) is less than 0, the
compound is more hydrophilic, meaning that the compound is more
soluble in an aqueous phase.
[0138] APIs suitable for use in embodiments of the present
invention generally include any drug that (1) is suitable or
intended for extended release in a body of a patient for a period
of at least about one week up to a period of at least about six
months, and (2) does not chemically interact with the acid end
groups of the biodegradable liquid polymer. Where the API is
ionizable, a pKa of the API is typically greater than about 3 and
less than about 8.5.
[0139] A further consideration in the design of the formulations of
the present invention is the chemical and physical stability of the
API in the formulation as a function of temperature. For example,
although formulations according to the present invention may be
administered at approximately room temperature and may be subjected
to human body temperature for a period of up to about six months,
the formulations of the present invention may often be subjected to
electron-beam ("e-beam") irradiation to sterilize the formulations
for use in humans. The temperature of the formulation during e-beam
processing may reach as high as 20.degree. C., or as high as near
body temperature (e.g., 34.degree. C., 35.degree. C., 36.degree.
C., 37.degree. C., 38.degree. C. or higher), and in some
circumstances could reach as high as 45.degree. C., unless the
temperature is controlled by using refrigerated processing or by
using split dose processing methods. It is important for the API of
choice to be chemically and physically stable within the
formulation at ambient temperature and at body temperatures, and in
one embodiment, also at the higher temperatures associated with,
for example, certain e-beam irradiation processes or other
processes which may expose the liquid polymer formulation to an
elevated temperature for a period of time. Similarly, because
formulations of the present invention may be stored for weeks or
months at ambient temperatures or under refrigeration, chemical and
physical stability of the API within the formulations in this lower
temperature range is also an element of the invention. As disclosed
more fully throughout this Detailed Description, formulations
comprising drugs meeting chemical and physical stability
requirements across the full range of applicable temperatures
include, but are by no means limited to, liquid polymer
formulations comprising testosterone, hormones and steroids other
than testosterone, APIs having similar low solubility in aqueous
environments as testosterone undecanoate, and pharmaceutically
acceptable salts and esters of any of such APIs.
[0140] In one embodiment, the API is in substantially solid form in
the liquid polymer and solvent(s) composition at temperatures up to
body temperature (e.g., about 36.5.degree. C. to about 37.5.degree.
C. (about 97.7.degree. F. to about 99.5.degree. F.)). In one
embodiment, the API is in substantially solid form in the liquid
polymer and solvent(s) composition at temperatures up to at least
about 36.degree. C. In one embodiment, the API is in substantially
solid form in the liquid polymer and solvent(s) composition at
temperatures up to at least about 37.degree. C. In one embodiment,
the API is in substantially solid form in the liquid polymer and
solvent(s) composition at temperatures up to at least about
38.degree. C. In one embodiment, the API is in substantially solid
form in the liquid polymer and solvent(s) composition at
temperatures up to at least about 39.degree. C. In one embodiment,
the API is in substantially solid form in the liquid polymer and
solvent(s) composition at temperatures up to at least about
40.degree. C. In one embodiment, the API is in substantially solid
form in the liquid polymer and solvent(s) composition at
temperatures up to at least about 41.degree. C. In one embodiment,
the API is in substantially solid form in the liquid polymer and
solvent(s) composition at temperatures up to at least about
42.degree. C. In one embodiment, the API is in substantially solid
form in the liquid polymer and solvent(s) composition at
temperatures up to at least about 43.degree. C. In one embodiment,
the API is in substantially solid form in the liquid polymer and
solvent(s) composition at temperatures up to at least about
44.degree. C. In one embodiment, the API is in substantially solid
form in the liquid polymer and solvent(s) composition at
temperatures up to at least about 45.degree. C. In one embodiment,
the API is in substantially solid form in the liquid polymer and
solvent(s) composition at a temperature range spanning from
refrigeration temperature (e.g., 2-8.degree. C.) or lower up to
body temperature, or in other embodiments up to any temperature
between 36.degree. C. and 45.degree. C. or higher, in 0.1.degree.
C. increments. In one embodiment, the temperature at which the API
becomes fully dissolved in the polymer and solvent or combination
or mixture of solvents, and the formulation thus becomes a
solution, is 45.degree. C. or higher (e.g., 46.degree. C.,
47.degree. C., 48.degree. C., 49.degree. C., 50.degree. C.,
51.degree. C., 52.degree. C., 53.degree. C., 54.degree. C.,
55.degree. C., or higher than 55.degree. C.).
[0141] In one embodiment, the API in a liquid polymer formulation
of the invention is in solution in the formulation. In one
embodiment, the API in an liquid polymer formulation of the
invention is in solution in the formulation at a temperature range
spanning from refrigeration temperature (e.g., 2-8.degree. C.) or
lower up to body temperature, or in other embodiments up to any
temperature between 36.degree. C. and 45.degree. C. or higher, in
0.1.degree. C. increments.
[0142] APIs (also referred to herein as drugs or active
pharmaceutical agents) that are suitable for the present
application are biologically active agents that provide a
biological effect and that act locally or systemically in the
treatment, therapy, cure and/or prevention of a disease, disorder,
or other ailment, or otherwise provide a health or medical benefit
to a subject. Examples of such drugs include, without limitation,
antimicrobials, anti-infectives, anti-parasitic drugs such as
avermectins, anti-allergenics, steroidal anti-inflammatory agents,
non-steroidal anti-inflammatory agents, anti-tumor agents,
anticancer drugs, decongestants, miotics, anti-cholinergics,
sympathomimetics, sedatives, hypnotics, psychic energizers,
tranquilizers, endocrine/metabolic agents, hormones (e.g. androgen,
anti-estrogen, estrogen, gonadotropin-releasing hormone analogues,
testosterone and progesterone), drugs for the treatment of
diabetes, drugs for the treatment of dementia (e.g. Alzheimer's
disease), GLP-1 agonists, androgenic steroids, estrogens,
progestational agents, LHRH agonists and antagonists,
somatotropins, narcotic antagonists, prostaglandins, analgesics,
antispasmodics, antimalarials, antihistamines, cardioactive agents,
antiparkinsonian agents, antihypertensive agents, anti-virals,
antipsychotics, immunosuppressants, anesthetics, antifungals,
antiproliferatives, anticoagulants, antipyretics, antispasmodics,
and nutritional agents. APIs of the foregoing classes and specific
APIs described herein can be administered in various forms,
including as base form, salts, esters, complexes, prodrugs and
analogs of the foregoing.
[0143] API's useful in the invention include a small molecule
organic compound. The small molecule drug may be a hydrophobic
drug, such as corticosteroids such as prednisone, prednisolone,
beclomethasone, fluticasone, methylprednisone, triamcinolone,
clobetasol, halobetasol, and dexamethasone; azole medications such
as metronidazole, fluconazole, ketoconazole, itraconazole,
miconazole, dimetridazole, secnidazole, ornidazole, tinidazole,
carnidazole, and panidazole; sex steroids such as testosterone,
estrogens such as estradiol, and progestins, including esters
thereof; statin drugs such as atorvastatin, simvastatin,
fluvastatin, lovastatin, pitavastatin, pravastatin, and
rosuvastatin; and antiandrogen drugs such as abiraterone,
galeterone, orteronel, and enzalutamide and salts, esters,
complexes, prodrugs and analogs of the foregoing.
[0144] Examples of specific additional drugs that may be utilized
include hydrophilic and hydrophobic small molecule drugs such as
rivastigmine tartrate, cisplatin, carboplatin, paclitaxel,
rapamycin, tacrolimus (fujimycin), bortezomib, trametinib,
methotrexate, riociguat, macitentan, sumatriptan, anastozole,
fulvestrant, exemestane, misoprostol, follicle-stimulating hormone,
axitinib, paricalcitol, pomalidomide, dustasteride, doxycycline,
doxorubicin, ciprofloxacin, quinolone, ivermectin, eprinomectin,
doramectin, leflunomide, teriflunomide, haloperidol, diazepam,
risperidone, olanzapine, amisulpride, aripiprazole, asenapine,
clopazine, iloperidone, lurasidone, paliperidone, quetiapine,
ziprasidone, bupivacaine, lidocaine, ropivacaine, naltrexone,
fentanyl, buprenorphine, butorphanol, loperamide, fingolimod, and
salts, complexes, prodrugs, and analogs thereof.
[0145] One suitable drug that may be utilized in the present
invention is testosterone or an ester thereof, including but not
limited to testosterone undecanoate, or TU (also known as
testosterone undecylate), testosterone cypionate (or TC),
testosterone propionate, testosterone enanthate, and testosterone
busciclate. Testosterone undecanoate is an ester of the hormone
testosterone used in androgen replacement therapy, primarily for
the treatment of male hypogonadism. Testosterone cypionate and
other esters of testosterone, as well as testosterone base drug can
be used for similar or the same indications. Testosterone
undecanoate as well as testosterone cypionate, or testosterone base
drug, or other forms of testosterone, may also be used as a male
contraceptive, or in transgender (female-to-male) hormone
therapy.
[0146] In some embodiments of the present invention, the API can be
a prodrug, such as, by way of non-limiting example, testosterone
undecanoate (TU). Where the API is a prodrug, the drug may be,
inter alia, a hydrophobic salt or covalently bound ester of the
corresponding drug, or bound to the polymer itself. Providing a
prodrug as the API may provide important advantages or benefits in
certain applications; by way of non-limiting example, providing the
API as a prodrug may improve the stability of the formulation (e.g.
during storage or irradiation, or after delivery in vivo), delay
the release of the active form of the drug, affect or modify the
solubility of the drug in the formulation, and/or extend or
otherwise modify the duration of action of the drug. Where the
prodrug is a covalently bound ester of the corresponding drug, the
ester is often hydrolyzed in vivo to the corresponding carboxylic
acid, which is then removed to convert the drug to its active form.
This mechanism may be particularly beneficial where a low burst
release and/or low peak plasma concentration of the drug is
desirable, as in the case, by way of non-limiting example, of TU.
In some embodiments, a desired release profile may be obtained by
providing a mixture of a prodrug and the corresponding drug, in a
predetermined ratio, as the API.
[0147] In some embodiments of the present invention, the API may be
provided in crystalline form. In these embodiments, a selection of
API crystal shape, or habit, may be another important consideration
in the preparation of the LPT formulation, as different crystal
habits may result in different release profiles. The selection of
crystal habit will largely depend upon the API and desired release
profile, but in general, the crystal habit should be stable
throughout all manufacturing, shipping, and delivery conditions,
e.g. during LPT formulation preparation, e-beam irradiation,
shipping and storage, mixing, injection, etc. Additionally,
different crystal habits may be more or less likely to form
hydrates or polymorphs, which may be desirable or undesirable
depending upon application, but it is generally advantageous that
the transition into the hydrate or polymorph be predictable and/or
controllable. Selection of a crystal habit can be based on these
and other considerations. In some embodiments, the API is in a
crystalline form having a block-like crystal habit or a needle-like
crystal habit.
[0148] A desired particle size, or distribution of particle sizes,
of the API will largely depend upon the API and the desired release
profile. In general, a smaller particle size will result in more
rapid release of the API in vivo (i.e., shorter duration of
release) and/or a larger burst and corresponding higher peak
concentration in vivo, while a larger particle size will result in
slower release of the API in vivo (i.e., longer duration of
release) and/or a smaller burst and corresponding lower peak
concentration in vivo. Where the LPT formulation is an injectable
formulation, the gauge of the needle used to inject the formulation
may also be an important consideration in selecting a particle
size, because large API particles may clog a large-gauge (i.e.
small-diameter) needle or require excessive injection force. In
some embodiments, a bimodal particle size distribution may provide
an advantageous release profile or other desirable effect; by way
of non-limiting example, and without wishing to be bound by any
particular theory, it may be possible that smaller particles may
cause rapid drug release (e.g. by faster release from a depot
and/or faster solubilization upon release and/or modification of
fluid channels in the depot) to provide an initial therapeutic
effect, and larger particles may be released later to provide an
extended therapeutic effect. Embodiments may also comprise
particles of the API that have been encapsulated in, e.g., a
microsphere or lipid sphere, which may provide an additional
mechanism for controlling release of the API in vivo.
[0149] As used herein, unless otherwise specified, the term
"particle size" refers to a median particle size determined by
volume-based particle size measurements, such as, by way of
non-limiting example, by use of a laser diffraction particle size
analyzer such as a Malvern Mastersizer.RTM. instrument; such
particle sizes may also be referred to as "D.sub.v,50" values.
Further, as used herein, unless otherwise specified, the term
"span" refers to the difference between a 90th percentile particle
size (referred to as "D.sub.v,90") and a 10th percentile particle
size (referred to as "D.sub.v,10"), divided by the 50th percentile
particle size; thus, the span of a volume of particles can be
interpreted as a measure of how broadly distributed particle sizes
are within the volume. In various embodiments, the API will have a
median particle size (D.sub.v,50) of between about 10 .mu.m and
about 200 between about 10 .mu.m and about 180 between about 10
.mu.m and about 160 between about 10 .mu.m and about 140 .mu.m,
between about 10 .mu.m and about 120 .mu.m, between about 10 .mu.m
and about 100 .mu.m, between about 15 .mu.m and about 100 .mu.m,
between about 15 .mu.m and about 90 .mu.m, between about 15 .mu.m
and about 80 .mu.m, between about 20 .mu.m and about 70 .mu.m,
between about 20 .mu.m and about 60 .mu.m, between about 25 .mu.m
and about 50 .mu.m, between about 30 .mu.m and about 90 .mu.m,
between about 40 .mu.m and about 90 .mu.m, between about 50 .mu.m
and about 90 .mu.m, between about 60 .mu.m and about 90 .mu.m, or
between about 70 .mu.m and about 90 .mu.m. In other embodiments,
the median particle size of the active pharmaceutical agent in
compositions of the invention can range from any whole number to
any other whole number within the range of from about 1 .mu.m and
about 250 .mu.m. Additionally, in various embodiments, the API may
have a particle size span of between about 0.1 and about 8, or
between about 0.5 and about 8, or between about 1 and about 8, or
between about 1.5 and about 8, or between about 2 and about 7, or
between about 3 and about 6, or between about 4 and about 5, or
about 4.5, or between about 1.5 and about 5, or between about 1.5
and about 6, or between about 2 and about 6, or between about 2 and
about 5, or between about 2 and about 4, or about 3, or
alternatively about any tenth of a whole number between about 1 and
about 8.
[0150] Yet another consideration in the preparation of LPT
formulations according to the present invention is the choice of
milling techniques used to prepare the API. Such techniques
include, by way of non-limiting example, ball milling, cryomilling,
cutter milling, homogenization, jet milling (also known as fluid
energy milling), mortar-and-pestle grinding, nano-milling or wet
milling followed by lyophilization or filtration or drying, roller
milling, or runner milling. In many embodiments, jet milling will
be the most desirable of these techniques due to its temperature
control, reduced risk of contamination, and scalability, but
techniques may be selected from among these and others based on the
needs of a given application. As is described in further detail in
the Examples, the present inventors have found that jet milling,
also known as fluid energy milling, is an advantageous milling
technique for providing API particles of a desired size. Among the
benefits of jet milling in LPT formulations are (1) reduced risk of
contamination with the milling medium, because the API comes into
contact only with nitrogen gas; (2) low heat generation, which
helps to keep the temperature of API particles below their melting
point during milling; and (3) scalability to produce large
quantities of API particles. The present inventors have also
investigated nano-milling in water followed by lyophilization, and
while this method may be used, it is less advantageous than jet
milling for several reasons: the requirement for multiple pieces of
equipment, the addition of wetting surfactants that may contaminate
the API after lyophilization, the inclusion of residual water that
may adversely affect polymer stability, etc. The present inventors
have further investigated homogenization as a method for
controlling particle size, and have found that it is less desirable
than jet milling as the sole technique for particle size control,
due to its relatively high heat generation and its inability to
reduce particle size below an asymptotic limit, but may be
desirable in combination with jet milling or other techniques
because it is effective to break up clumps of the API and improves
homogeneity of the resulting suspension. In general, the present
inventors have found that mechanical micronization and milling
techniques are generally more suitable than recrystallization
techniques in LPT-TU formulations, as recrystallization risks
introducing residual solvents and co-crystals that may affect
formulation behavior and safety.
[0151] The concentration of active pharmaceutical agent in
compositions of the invention depends on the drug that is included
in the composition and may range from 0.1% to 50% by weight of the
composition or higher. Typically, the concentration of agent in the
composition is between 10% and 50% by weight of the composition,
such as between 15% and 45% by weight of the composition, between
15% and 35% by weight of the composition, between 15% and 25% by
weight of the composition, between 20% and 40% by weight of the
composition, between 25% and 35% by weight of the composition,
about 10% by weight of the composition, about 15% by weight of the
composition, about 20% by weight of the composition, about 25% by
weight of the composition, or about 30% by weight of the
composition. In other embodiments, the amount of active
pharmaceutical agent in compositions of the invention can range
from any whole number percent to any other whole number percent
within the range of from about 1 percent to about 50 percent by
weight. In some embodiments, the concentration of the active
pharmaceutical agent is no more than about 25% by weight.
[0152] Because a beneficial characteristic of the compositions
disclosed herein is improved extended release of an active
pharmaceutical agent, the amount of active pharmaceutical agent
should be suitable for long term treatment with the agent in
accordance with the time frames disclosed herein. Other embodiments
of the invention include single dosage formulations of the liquid
polymer pharmaceutical composition which include the liquid polymer
composition as described herein with an amount of an active
pharmaceutical agent suitable for extended release. For example,
such single dosage formulations can include sufficient active
pharmaceutical agent for treatment of a patient for at least three
days, at least one week, at least two weeks, at least three weeks,
at least four weeks, at least one month, at least two months, at
least three months, at least four months, at least five months, at
least six months, at least nine months, or at least one year.
Compositions may be administered repeatedly as needed (e.g. every
week, every 2 weeks, every month, every two months, every three
months, every four months, every five months, every six months,
etc.). Other dosage patterns are also suitable for use with the
formulations of the invention, such as alternating dosing patterns
(e.g., at Day 0, at 2 weeks, and then every month thereafter; or at
Day 0, at 1 month and then every 3 months thereafter, etc.).
[0153] When the API used in a liquid polymer formulation of the
invention is TU or TC (or another testosterone ester or
testosterone base), the amount of TU or TC (or another testosterone
ester or testosterone base) to administer to a subject should be
sufficient to achieve the desired therapeutic effect, e.g., to
provide testosterone supplementation in the eugonadal range
(10.4-34.7 nmol/L or 3-10 ng/mL testosterone in plasma (see, e.g.,
Basaria or Morgentaler et al., supra); to treat or reduce the
symptoms of androgen deficiency; to treat or reduce the symptoms of
male hypergonadism; as an adjunct therapy for transgender men or
gender reassignment; or as birth control. For example, as
previously known and described in the art, testosterone
undecanoate, when administered as an oil-based solution of the
prior art, may be administered to males over 18 years of age as an
initial 750 mg, 3 mL intramuscular dose, followed by another 750
mg, 3 mL intramuscular dose after four weeks and further 750 mg, 3
mL intramuscular doses every ten weeks thereafter. Alternatively,
such a solution can be administered in a 1000 mg dose once every 12
weeks with no loading dose.
[0154] According to embodiments of the present invention,
testosterone undecanoate (or testosterone or another testosterone
ester, including, but not limited to, testosterone cypionate,
testosterone enanthanate, or testosterone proprionate), when
administered in the LPT formulations of the present invention, may
be administered to a patient as a dose of between about 25 mg and
about 1000 mg, or between about 100 mg and 1000 mg, or between
about 150 mg and 1000 mg, or between about 200 mg and 1000 mg, or
between about 250 mg and 1000 mg, or between about 500 mg and 1000
mg, or between about 750 mg and 1000 mg, or alternatively any whole
number of milligrams between about 25 mg and about 1000 mg,
including, but not limited to 100 mg, 150 mg, 200 mg, 250 mg, 300
mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg,
750 mg, or higher. The amount of testosterone undecanoate (or
testosterone or another testosterone ester), when administered in
the LPT formulations of the present invention, can be sufficient to
provide the desired therapeutic effect when administered weekly,
biweekly, monthly, every two months, every three months, every four
months, every five months, or every six months, every seven months,
every eight months, every nine months, every ten months, every
eleven months, or every twelve months, and for as long as
testosterone supplementation is required. Testosterone undecanoate
(or testosterone or another testosterone ester) can be provided in
an LPT formulation of the invention in an amount sufficient to
provide one or more initial loading doses at shorter intervals
(e.g., weekly, biweekly or monthly), followed by maintenance doses,
where the amount of API provided or the interval of the dosing
increases, or under any alternative dosing regimen, such as by
administering an initial larger dose followed by smaller
maintenance doses, or by altering larger and smaller doses.
[0155] Additionally or alternatively, testosterone undecanoate (or
testosterone or another testosterone ester), when administered in
the LPT formulations of the present invention, may be administered
at times and in amounts sufficient to achieve a serum testosterone
concentration of between about 0.5 ng/mL and about 20 ng/mL, or
between about 1 ng/mL and about 15 ng/mL, or between about 2 ng/mL
and about 15 ng/mL, or between about 3 ng/mL and about 10 ng/mL, or
between about 4 ng/mL and about 9 ng/mL, or between about 5 ng/mL
and about 8 ng/mL, or between about 6 ng/mL and about 7 ng/mL, or
about 6.5 ng/mL.
Biocompatible Solvents for Use in the Invention
[0156] LPT pharmaceutical formulations according to the present
invention comprise at least one biocompatible solvent. As noted
above, in some embodiments the API may be substantially in solid
form (i.e. solid particles of the API are suspended in the liquid
polymer/solvent composition), while in other embodiments the API
may be substantially or fully dissolved in the liquid
polymer/solvent composition. As used herein unless otherwise noted,
use of the term "suspension" when referring to a composition of the
invention may refer to formulations in which at least about 10%, or
at least about 15%, or at least about 20%, or at least about 25%,
or at least about 30%, or at least about 35%, or at least about
40%, or at least about 45%, or at least about 50%, or at least
about 55%, or at least about 60%, or at least about 65%, or at
least about 70%, or at least about 75%, at least about 80%, or at
least about 85%, or at least about 90%, or at least about 95%, or
at least about 96%, or at least about 97%, or at least about 98%,
or at least about 99% of the API is in the form of solid particles
suspended in the liquid polymer and solvent composition.
Description of an API herein as being "substantially in solid form"
or "substantially in suspension" in a formulation refers to
formulations in which at least about 50%, or at least about 55%, or
at least about 60%, or at least about 65%, or at least about 70%,
or at least about 75%, at least about 80%, or at least about 85%,
or at least about 90%, or at least about 95%, or at least about
96%, or at least about 97%, or at least about 98%, or at least
about 99% of the API is in the form of solid particles suspended in
the liquid polymer and solvent composition.
[0157] As used herein unless otherwise noted, use of the term
"solution" or description of an API as being "dissolved" in a
formulation, refers to formulations in which at least 99% of the
API is dissolved in the liquid polymer/solvent composition.
[0158] Solvents and co-solvents suitable for use in embodiments of
the present invention include, by way of non-limiting example,
acetone, benzyl benzoate, butyrolactone, .epsilon.-caprolactone,
N-cycylohexyl-2-pyrrolidone, diethylene glycol monomethyl ether,
dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide (DMSO),
ethyl acetate, ethyl lactate, N-ethyl-2-pyrrolidone, glycerol
formal, glycofurol, N-hydroxyethyl-2-pyrrolidone, isopropylidene
glycerol, lactic acid, methoxypolyethylene glycol, methoxypropylene
glycol, methyl acetate, methyl ethyl ketone, methyl lactate,
N-methyl-2-pyrrolidone (NMP), low-molecular weight (MW)
polyethylene glycol (PEG), polysorbate 80, polysorbate 60,
polysorbate 40, polysorbate 20, polyoxyl 35 hydrogenated castor
oil, polyoxyl 40 hydrogenated castor oil, sorbitan monolaurate,
sorbitan monostearate, sorbitan monooleate, benzyl alcohol,
isopropanol, tert-butanol, n-propanol, propylene glycol,
2-pyrrolidone, .alpha.-tocopherol, triacetin, tributyl citrate,
acetyl tributyl citrate, acetyl triethyl citrate, triethyl citrate,
esters thereof, and combinations thereof. One or more of these and
other solvents, including but not limited to benzyl benzoate, may
form a suspension when provided in relatively small quantities
and/or when used as a co-solvent or additive, and a solution when
provided in relatively large quantities.
[0159] The solvent system used in an LPT formulation of the
invention may comprise a combination or mixture of two or more
compounds or components, and in some embodiments, the combination
may include NMP or DMSO in combination with another component such
as low molecular weight PEG (e.g. PEG 300 or PEG 400). The
additional component, which may be generally referred to as an
additive or co-solvent, e.g. PEG (by way of non-limiting example),
may have any one of several effects, including but not limited to a
true solvent effect (i.e. the API dissolves or is suspended in the
additional component) or an effect by which the additional
component does not directly dissolve or suspend the API but
improves the degree to which the API is dissolved or suspended in
the other solvent(s) (e.g. the additional component acts as a
co-solvent, miscibility aid, solubilizer, non-solvent, or
surfactant).
[0160] In one embodiment, an LPT formulation of the invention
comprises an additional component that is a solubilizer, which is
useful for increasing the solubility of the API in the LPT
formulation, particularly in vivo. The presence of such a
solubilizer, without being bound by theory, will reduce likelihood
that the API (which has relatively low solubility in aqueous media,
and/or is relatively hydrophobic) will crystalize, particularly in
vivo when the solvent system dissipates from the formulation. In
one aspect, the solubilizer is selected to have a release profile
in the LPT formulation similar to that of the API, so that the
release of the API and solubilizer are somewhat synchronous. For
example, if the API is in a fatty acid ester form, such as
testosterone undecanoate, then one could select a solubilizer that
is a sucrose ester of a medium chain fatty acid ester, such as
sucrose laurate. Examples of solubilizers useful in the present
invention include solubilizers useful for parenteral injection, and
include, but are not limited to, surfactants and other
solubilizers, such as Poloxamer 188, sorbitan trioleate, lecithin
(e.g., soya or egg), D-.alpha.-tocopherol polyethylene glycol
succinate (e.g., Vitamin E TPGS), sugar-based esters or ethers
(e.g., sugar acid esters of fatty alcohols or sugar alcohol esters
of fatty acids, including, but not limited to, sucrose cocoate,
sucrose stearate, sucrose laurate, etc,), amino acid-based
solubility enhancers (e.g., proline, arginine, DL-methionine),
protein-based solubility enhancers (e.g., hydrophobins) and
combinations thereof. The use of sugar-based esters and ethers as
solubilizers in parenteral pharmaceutical formulations is
described, for example, in U.S. Pat. No. 8,541,360, which is
incorporated herein by reference in its entirety.
[0161] When present, the additional component, e.g. PEG, may, in
embodiments, be provided in any amount between about 15 wt % and 45
wt %, or between about 17 wt % and about 33 wt %, or between about
19 wt % and about 31 wt %, or between about 21 wt % and about 29 wt
%, or between about 23 wt % and about 27 wt % of the formulation,
or alternatively as any whole number percentage by weight of the
formulation between about 15 wt % and about 45 wt %. In some
embodiments the additional component may be relatively miscible
with one or more other solvent(s), while in other embodiments the
additional component may be relatively immiscible with one or more
other solvents.
[0162] In embodiments of the present invention, the solvent, or
combination or mixture of solvents and/or co-solvents, will
generally comprise between about 20 wt % and about 95 wt % of the
formulation, or between about 35 wt % and about 80 wt % of the
formulation, or between about 45 wt % and about 65 wt % of the
formulation, or between about 45 wt % and about 55 wt % of the
formulation, or about 50 wt % of the formulation, or alternatively
the solvent or combination or mixture of solvents and/or
co-solvents can range from any whole number percentage by weight of
the formulation to any other whole number percentage by weight of
the formulation between about 20 wt % and about 95 wt %. Where the
solvent comprises two or more compounds, any two compounds may be
present in any weight ratio between about 99:1 and about 1:99, or
between about 90:10 and about 10:90, or between about 80:20 and
about 20:80, or between about 30:70 and about 70:30, or between
about 40:60 and about 60:40, or about 50:50, or alternatively in
any weight ratio X:Y where each of X and Y is a whole number
between about 1 and about 99 and the sum of X and Y is 100.
[0163] In one embodiment, the solvent can be benzyl benzoate, in an
amount between about 50 wt % and about 75 wt % of the formulation,
or between about 55 wt % and about 70 wt % of the formulation, or
between about 60 wt % and about 65 wt % of the formulation, or
about 65 wt % of the formulation.
[0164] In another embodiment, the solvent can be a mixture of DMSO
and low molecular weight PEG (e.g., PEG having a molecular weight
of about 400 daltons), where the DMSO is included in an amount
between about 15 wt % and about 55 wt % of the formulation, or
between about 20 wt % and about 50 wt %, or between about 25 wt %
and about 45 wt %, or between about 30 wt % and about 40 wt %; or
at about 35 wt % of the formulation; and where the PEG is included
in an amount between about 5 wt % and about 35 wt % of the
formulation, or between about 10 wt % and about 20 wt %, or about
15 wt % of the formulation.
[0165] In yet another embodiment, the solvent may be a mixture of
NMP and low molecular weight PEG (e.g., PEG having a molecular
weight of about 300 daltons), where the NMP is included in an
amount between about 15 wt % and about 50 wt % of the formulation,
or between about 20 wt % and about 30 wt %, or about 25 wt % of the
formuation, and where the PEG is included in an amount between
about 15 wt % and about 35 wt % of the formulation, or between
about 20 wt % and about 30 wt %, or about 25 wt % of the
formulation.
[0166] Where the solvent is a combination or mixture of solvents,
any two of the solvents in the mixture may be present in any weight
ratio between about 1:99 and about 99:1. Where the solvent is a
mixture of PEG and either NMP or DMSO, the ratio of PEG to NMP or
DMSO is between about 20:80 and about 80:20, or between about 30:70
and about 70:30, or between about 35:65 and about 65:35, or about
50:50, or alternatively any ratio of whole numbers X and Y, where
each of X and Y is at least about 1 and no more than about 99 and
the sum of X and Y is 100.
[0167] For LPT formulations of the invention in which the API is
not soluble or completely soluble in the formulation, the API is in
suspension in the formulation rather than in a solution. In these
embodiments, the sedimentation coefficient or rate of separation of
the API and/or the polymer in the solvent system is advantageously
on the order of days or weeks because this allows a user to mix the
formulation to ensure homogeneity for minutes or hours, in some
embodiments at least about 30 minutes, in advance of injection. In
these and other embodiments, there may be no visually apparent
separation of the API, the polymer, and/or the solvent from a
remainder of the formulation for a period of at least about one
month after initial suspension, or at least about two months after
initial suspension, or at least about three months after initial
suspension, or at least about four months after initial suspension,
or at least about five months after initial suspension, or at least
about six months after initial suspension.
Biocompatible Liquid Polymers for Use in the Invention
[0168] The liquid polymer compositions of the invention comprise a
biodegradable liquid polymer. In some embodiments, the polymers
have a carboxylic acid end group, such as a glycolic acid end
group, and may be made by standard chain-growth polymerization
techniques, by combining one or more alkene or alicyclic monomers
with a carboxylic acid or water, often a hydroxy acid, in the
presence of a suitable catalyst, such as tin, for example in the
form of stannous octanoate. Carboxylic acids that are suitable are
those that contain an alkyl chain, a nucleophile, and are soluble
in the monomer used to make the polymer or a combination of the
monomer and solvent. Examples of suitable initiators include, but
are not limited to, GHB (gamma-hydroxybutyric acid), lactic acid,
glycolic acid, citric acid, and water. Typically, a biodegradable
polymer with an acid end group is made by the ring opening
polymerization of monomers, such as lactide and/or caprolactone,
which is initiated by water or a carboxylic acid compound of the
formula Nu-R--COOH where Nu is a nucleophilic moiety, such as an
amine or hydroxyl, R is any organic moiety, and the --COOH is a
carboxylic acid functionality. The nucleophilic moiety of the
molecule acts to initiate the ring opening polymerization in the
presence of a catalyst and heat, producing a polymer with a
carboxylic acid functionality on one end. A representative
polymerization equation is shown below as Formula A.
##STR00001##
[0169] Alternatively, a carboxylic acid end group may be created on
the end of a polymer chain by post-polymerization modification.
[0170] In addition to carboxylic acid end groups, liquid polymers
according to the present invention may have any other suitable type
of end group, including but not limited to ester end groups and
hydroxyl end groups.
[0171] The liquid polymers that can be used according to the
present invention are biodegradable, and remain in a liquid form,
i.e. undergo continuous deformation under a shearing stress greater
than zero and/or greater than a yield stress, at room temperature
(e.g., at approximately 25.degree. C.) up to body temperature
(e.g., at approximately 37.degree. C.), even after dissipation of
the solvent from the polymer composition, such as when the polymer
composition is exposed to an aqueous or largely aqueous environment
(e.g. in vivo). The characteristic of being liquid is achieved by
control of the molecular weight of the polymer and the monomer
selection and ratio. In addition, the liquid polymer can have a
pre-injection bulk viscosity that allows the composition to be
easily administered, and in some embodiments effective to provide a
desired controlled release profile of a biologically active agent
from the implanted material. Because the liquid polymers are liquid
at room and body temperature, they allow the use of lower
concentrations of the biocompatible solvent to be used in the
composition to provide a syringeable formulation compared to
polymer/solvent compositions prepared with solid polymers.
[0172] Examples of suitable polymers that can be used in this
application include polylactic acid, polyglycolic acid, polylactide
(DL-lactide, D-lactide, L-lactide), polyglycolide,
polycaprolactones, polyanhydrides, polyamides, polyurethanes,
polyesteramides, polyorthoesters, polydioxanones, polyacetals,
polyketals, polycarbonates, polyphosphazenes, polyhydroxybutyrates,
polyhydroxyvalerates, polyalkylene oxalates, polyalkylene
succinates, poly(malic acid), polyethylene glycol, hyaluronic acid,
chitin and chitosan, and copolymers, terpolymers, and combinations
or mixtures of the above materials. In one embodiment, the liquid
polymer is selected from the group consisting of a polylactide, a
polyglycolide, a polycaprolactone, a poly(trimethylene carbonate),
a polydioxanone, a copolymer thereof, a terpolymer thereof, or any
combination thereof. Suitable materials include, but are not
limited to, those polymers, copolymers or terpolymers made with
lactide, glycolide, caprolactone, p-dioxanone, trimethylene
carbonate, 1,5-dioxepan-2-one, 1,4-dioxepan-2-one, ethylene oxide,
propylene oxide, sebacic anhydride, diketene acetals/diols, and
lactic acid with lower molecular weights and amorphous regions to
limit crystallinity and subsequent solidification.
[0173] Non-limiting examples of suitable liquid polymers according
to the invention include copolymers of DL-lactide and
.epsilon.-caprolactone with molar ratios of lactide/caprolactone
ranging from about 75/25 to about 25/75 and optionally with
inherent viscosities as determined in a 0.10 g/dL solution of
hexafluoroisopropanol (HFIP) at 25.degree. C. from about 0.06 to
about 0.38 dL/g, copolymers of caprolactone and 1,4-dioxanone with
molar ratios of about 70/30 to about 40/60 and optionally with
inherent viscosities of about 0.08 to about 0.24 dL/g, lactide and
trimethylene carbonate copolymers such as 75/25
poly(DL-lactide-co-trimethylene carbonate), copolymers of
caprolactone and trimethylene carbonate with molar ratios of about
90/10 to about 50/50 and optionally with inherent viscosities of
about 0.09 to about 0.25 dL/g, and poly(L-lactic acid) optionally
with an inherent viscosity of about 0.06 dL/g, among others.
Generally, liquid polymers and liquid polymer compositions of the
invention can have an inherent viscosity as determined in a 0.10
g/dL solution of hexafluoroisopropanol at 25.degree. C. from 0.05
to 0.50 dL/g.
[0174] In embodiments of the composition, the biodegradable liquid
polymer is a copolymer of two monomers having a molar ratio of any
two whole numbers X to Y, where each of X and Y is at least about
25 and no more than about 75 and the sum of X and Y is 100. In one
embodiment, the molar ratio of the two monomers in the copolymer is
about 75/25.
[0175] In embodiments of the composition, a weight average
molecular weight of the biodegradable liquid polymer is between
about 1,000 daltons and about 25,000 daltons, or between about
5,000 daltons and about 25,000 daltons, or between about 6,000
daltons and about 24,000 daltons, or between about 7,000 daltons
and about 23,000 daltons, or between about 8,000 daltons and about
22,000 daltons, or between about 9,000 daltons and about 21,000
daltons, or between about 10,000 daltons and about 20,000 daltons,
or between about 11,000 daltons and about 19,000 daltons, or
between about 12,000 daltons and about 18,000 daltons, or between
about 13,000 daltons and about 17,000 daltons, or between about
14,000 daltons and about 16,000 daltons, or about 15,000 daltons.
The weight average molecular weight of the biodegradable liquid
polymer may be about 1,000 daltons, or about 2,000 daltons, or
about 3,000 daltons, or about 4,000 daltons, about 5,000 daltons,
or about 6,000 daltons, or about 7,000 daltons, or about 8,000
daltons, or about 9,000 daltons, or about 10,000 daltons, or about
11,000 daltons, or about 12,000 daltons, or about 13,000 daltons,
or about 14,000 daltons, or about 15,000 daltons, or about 16,000
daltons, or about 17,000 daltons, or about 18,000 daltons, or about
19,000 daltons, or about 20,000 daltons, or about 21,000 daltons,
or about 22,000 daltons, or about 23,000 daltons, or about 24,000
daltons, or about 25,000 daltons, or about 26,000 daltons, or about
27,000 daltons, or about 28,000 daltons, or about 29,000 daltons,
or about 30,000 daltons, or about 31,000 daltons, or about 32,000
daltons, or about 33,000 daltons, or about 34,000 daltons, or about
35,000 daltons.
[0176] In one embodiment, the biodegradable liquid polymer can have
a weight average molecule weight between about 1000 daltons and
about 35,000 daltons. Alternatively, the weight average molecular
weight of the biodegradable liquid polymer can be any whole number
of daltons between about 1,000 daltons and about 25,000 daltons, or
between about 1,000 and about 35,000 daltons.
[0177] In embodiments of the composition, the biodegradable liquid
polymer may make up between about 0.1 wt % and about 50 wt % of the
composition, or between about 5 wt % and about 45 wt % of the
composition, or between about 10 wt % and about 40 wt % of the
composition, or between about 15 wt % and about 35 wt % of the
composition, or between about 20 wt % and about 30 wt % of the
composition, or about 20 wt % of the composition, or about 25 wt %
of the composition, or about 30 wt % of the composition.
Alternatively, the biodegradable liquid polymer may make up any
whole-number weight percentage of the formulation between about 1
wt % and about 50 wt %, or may make up a range from any
whole-number weight percentage of the formulation to any other
whole-number weight percentage of the formulation with end points
between 1 wt % and 50 wt %.
[0178] The liquid polymers of the present invention can have a
polydispersity value of from about 1.30 to about 2.50, or from
about 1.35 to about 2.25, or from about 1.40 to about 2.00, or from
about 1.45 to about 1.75, or about 1.50, or alternatively any
twentieth of a whole number between about 1.30 and about 2.50.
[0179] Further examples of suitable liquid polymers of the
invention include biodegradable liquid polymers with at least about
25% lactide (including DL-lactide) residues, at least about 30%
lactide residues, at least about 35% lactide residues, at least
about 40% lactide residues, at least about 45% lactide residues, at
least about 50% lactide residues, at least about 55% lactide
residues, at least about 60% lactide residues, at least about 65%
lactide residues, at least about 70% lactide residues, or at least
about 75% lactide residues. Other examples of suitable liquid
polymers of the invention include biodegradable liquid polymers
with residues of comonomers selected from caprolactone,
trimethylene carbonate and combinations thereof in an amount at
least about 5% and no more than about 75%, no more than about 70%
such residues, no more than about 65% such residues, no more than
about 60% such residues, no more than about 55% such residues, no
more than about 50% such residues, no more than about 45% such
residues, no more than about 40% such residues, no more than about
35% such residues, no more than about 30% such residues, or no more
than about 25% such residues. Further embodiments include liquid
polymers of 75:25 DL-lactide:.epsilon.-caprolactone, 75:25
DL-lactide:trimethylene carbonate, 25:75
DL-lactide:.epsilon.-caprolactone, and 75:25
.epsilon.-caprolactone:trimethylene carbonate.
[0180] The biodegradable liquid polymers of the invention can also
be characterized as having at least one carboxylic acid end group.
Further, the polymers can have a ratio of monomer units to
carboxylic acid end groups that is between about 5:1 and about
90:1, between about 10:1 and about 90:1, between about 15:1 and
about 90:1, between about 20:1 and about 90:1, between about 30:1
and about 80:1, between about 40:1 and about 70:1, between about
50:1 and about 60:1, or about 55:1. Alternatively, the ratio of
monomer units to carboxylic acid end groups can be less than about
90:1, less than about 80:1, less than about 70:1, less than about
60:1, or less than about 55:1. The ratio of monomer units to
carboxylic acid end groups can range from any whole number ratio to
any other whole number ratio within the range of about 5:1 to about
90:1. The ratio of monomer units to carboxylic acid end groups
corresponds to a number-average molecular weight of the polymer,
which is equal to the weight-average molecular weight divided by
the polydispersity index.
[0181] As is described in detail throughout this disclosure,
various polymerization initiators can be selected when synthesizing
the polymer for LPT formulations. The present inventors have
generally found .alpha.-hydroxy acid initiators, and especially
glycolic acid, to be advantageous for use in LPT formulations
comprising testosterone or TU as the API.
Liquid Polymer Compositions of the Invention
[0182] The liquid polymer compositions of the invention comprise a
biodegradable liquid polymer, a biocompatible solvent or a
combination or mixture of solvents or solvents and co-solvents, and
an API, and are prepared by mixing or blending together the liquid
polymer(s) and the solvent(s), which can be performed by any method
at a temperature ranging from about 10-50.degree. C. (e.g., at
about 25.degree. C.) using a suitable device to achieve a
homogeneous, flowable liquid at room temperature. Examples of such
devices include a mechanical stirrer, a mixer, or a roller mill.
Because both the polymer and solvents are liquids, they may be
mixed over a period (e.g., hours or days) to form a homogeneous
solution or suspension.
[0183] In one embodiment, where the API is testosterone undecanoate
(TU) or testosterone cypionate (TC), the formulation may be a
suspension and may comprise between about 1 wt % and about 50 wt %,
or between about 15 wt % and about 35 wt %, of NMP; between about 1
wt % and about 50 wt %, or between about 15 wt % and about 35 wt %,
of low-MW PEG; between about 1 wt % and about 50 wt %, or between
about 15 wt % and about 35 wt %, of TU or TC; and between about 1
wt % and about 50 wt %, or between about 15 wt % and about 35 wt %,
of the biodegradable liquid polymer. The skilled artisan, in
practicing the present invention, will select appropriate specific
values for each component to ensure that the total amounts of all
four components sum to 100 wt %.
[0184] In another embodiment, where the API is TU or TC, the
formulation may be a suspension and may comprise between about 1 wt
% and about 50 wt %, or between about 15 wt % and about 35 wt %, of
DMSO; between about 1 wt % and about 50 wt %, or between about 15
wt % and about 35 wt %, of low-molecular weight PEG; between about
1 wt % and about 50 wt %, or between about 15 wt % and about 35 wt
%, of TU or TC; and between about 1 wt % and about 50 wt %, or
between about 15 wt % and about 35 wt %, of the biodegradable
liquid polymer. The skilled artisan, in practicing the present
invention, will select appropriate specific values for each
component to ensure that the total amounts of all four components
sum to 100 wt %.
[0185] In another embodiment, where the API is TU or TC, the
formulation may be a solution and may comprise between about 40 wt
% and about 90 wt %, or between about 55 wt % and about 75 wt %, of
benzyl benzoate; between about 1 wt % and about 50 wt %, or between
about 5 wt % and about 25 wt %, of TU or TC; and between about 1 wt
% and about 50 wt %, or between about 10 wt % and about 30 wt %, of
the biodegradable liquid polymer. The skilled artisan, in
practicing the present invention, will select appropriate specific
values for each component to ensure that the total amounts of all
three components sum to 100 wt %.
[0186] In addition to particle size, the viscosity of the LPT
formulation significantly affects the injection force necessary to
administer the formulation. In general, it is desirable, for the
purposes of patient comfort, to provide injections to the patient
using the largest needle gauge (i.e. smallest needle diameter)
possible, but a smaller needle requires a greater injection force
to inject the formulation. Accordingly, needle gauge and injection
force must be balanced against each other, and LPT formulations
according to the present invention must have a combination of
viscosity, particle size, and other factors that enables the
formulation to be delivered down an appropriately large-gauge (i.e.
small-diameter) needle by applying an appropriately moderate
injection force. To minimize pain to the patient, it is desirable
that LPT formulations according to the present invention be
delivered using at most a 16-gauge needle (inner diameter 1.194
mm), or at least an 18-gauge needle (inner diameter 0.838 mm), or
at least a 20-gauge needle (inner diameter 0.603 mm). The average
adult male human can generate 85 newtons of force in a pinching
motion using the thumb and forefingers, while the average adult
female human can generate about 48 newtons of force by the same
motion; it is thus desirable to provide LPT formulations having an
injection force of no more than about 48 newtons, to enable the
formulation to be administered by both men and women. Thus, by way
of non-limiting example, where the formulation is to be delivered
using a 20-gauge needle or by devices allowing similar injection
forces, to ensure that the formulation can be delivered by an
appropriate injection force, it may be advantageous that LPT
formulations according to the present invention have a viscosity at
room temperature of no more than about 5,000 cP, or no more than
about 4,500 cP, or no more than about 4,000 cP, or no more than
about 3,500 cP, or no more than about 3,000 cP, or no more than
about 2,500 cP, or no more than about 2,000 cP. Other viscosity
ranges may be advantageous for use with needles of other sizes.
[0187] LPT formulations of the present invention may be used for
controlled-release delivery of the API, and as a result may have
very high viscosities in vivo after dissipation of the solvent. By
way of non-limiting example, the LPT formulations of the present
invention may have viscosities under in vivo conditions, e.g. at
about 37.degree. C., of at least about 500 cP, or at least about
600 cP, or at least about 700 cP, or at least about 800 cP, or at
least about 900 cP, or at least about 1,000 cP, or at least about
2,000 cP, or at least about 3,000 cP, or at least about 4,000 cP,
or at least about 5,000 cP, or at least about 10,000 cP, or at
least about 15,000 cP, or at least about 20,000 cP, or at least
about 25,000 cP, or at least about 30,000 cP, or at least about
35,000 cP, or at least about 40,000 cP, or at least about 45,000
cP, or at least about 50,000 cP. Solvents may be selected to
provide a suitably low viscosity prior to administration and a
suitably high viscosity after administration; by way of
non-limiting example, LPT formulations may be injectable as a thin,
relatively inviscid (having no or negligible viscosity) liquid and
then greatly increase in viscosity in vivo after injection. As a
result of these very high in vivo viscosities and other factors,
including but not limited to polymer molecular weight, solvent, and
particle size and shape, LPT formulations of the present invention
may form a depot in vivo that persists in a patient's body; in some
embodiments, the depot may persist in the patient's body longer
than the release profile of the API remains in the therapeutic
range. By way of non-limiting example, an LPT formulation according
to the present invention may form a depot in vivo that provides the
API in the therapeutic range for about three months but that
persists in the patient's body for at least about five months. The
depot may have an in vivo viscosity that is much higher than a
viscosity of the LPT formulation; by way of non-limiting example,
an in vivo viscosity of the depot may, in some embodiments, be at
least about 5,000 cP.
[0188] In some embodiments, the LPT formulation may comprise an
additive to improve injectability, referred to as an "injectability
booster;" by way of non-limiting example, the additive may comprise
an enzyme, e.g. collagenase or hyaluronidase, to inhibit the
formation of aggregates.
[0189] In some embodiments, the LPT formulation may comprise an
additive to assist with the degradation of the polymer in situ
(e.g., in vivo) over time. For example, it may be desirable to
include an additive that ensures that the polymer completely
degrades by a particular time point after injection which is
commensurate with or shortly after the complete release of the API
from the polymer.
[0190] The present invention provides LPT formulations that remain
stable for an extended length of time under refrigeration, e.g.
2-8.degree. C., and/or formulations that remain stable for an
extended length of time at room temperature, e.g., 15-25.degree.
C., where "stability" refers to one or more of (1) negligible or
minimal change in polymer mass, (2) chemical and physical stability
of the API in the formulation (e.g., negligible or minimal change
in API content and/or particle size), and (3) solvent and/or
co-solvent content. In embodiments, there may be no more than about
10%, or no more than about 9%, or no more than about 8%, or no more
than about 7%, or no more than about 6%, or no more than about 5%,
or no more than about 4%, or no more than about 3%, or no more than
about 2%, or no more than about 1% change in the polymer molecular
weight, or no more than about 5 kDa, or no more than about 4 kDa,
or no more than about 3 kDa, or no more than about 2 kDa, or no
more than about 1 kDa change in polymer molecular weight, at
intended storage conditions over an intended shelf life or at
accelerated storage conditions over an abbreviated duration, and/or
an activity of the API may change by no more than about 15%, or no
more than about 14%, or no more than about 13%, or no more than
about 12%, or no more than about 11%, or no more than about 10%, or
no more than about 9%, or no more than about 8%, or no more than
about 7%, or no more than about 6%, or no more than about 5%, or no
more than about 4%, or no more than about 3%, or no more than about
2%, or no more than about 1% at intended storage conditions over an
intended shelf life. In general, increased shelf stability is
always desirable, and the shelf life of formulations of the present
invention at 5.degree. C. and/or at room temperature is, in
embodiments, at least about three months, or at least about six
months, or at least about nine months, or at least about twelve
months, or at least about fifteen months, or at least about
eighteen months, or at least about 21 months, or at least about 24
months. In some embodiments, the LPT formulation may be suitable to
be refrigerated for a longer period of time and then stored at room
temperature for a shorter period of time for user convenience; by
way of non-limiting example, LPT formulations according to the
present invention may be shelf-stable at 5.degree. C. for at least
about 24 months, and then shelf-stable for an additional time of at
least about one month at room temperature.
[0191] LPT formulations according to the present invention may be
administered intramuscularly or subcutaneously to provide a
systemic effect, or they may be administered by other means to
provide a local effect of the API. By way of non-limiting example,
LPT formulations may be administered in an articular region, a
cutaneous region, an ocular region, and/or a tumor site region
where it is desired that the API act locally rather than
systemically. One advantage of LPT formulations of the invention is
that, due to the liquid nature of the formulation, they form an
implant or depot that can be characterized as soft, malleable,
non-rigid, and/or non-solid. Such formulations, when administered
into, for example, an articular region or other region where
mobility or sensitivity may be an issue, result in the formation of
an implant or depot in vivo after administration that has physical
characteristics that allow the implant or depot to be better
tolerated and have much less impact on mobility than, for example,
a solid, hard implant.
[0192] Testosterone and esters thereof, especially TU or TC, are
particularly suitable APIs for use in embodiments of the present
invention. TU and/or TC in particular is a desirable API for use in
the present invention because it requires or greatly benefits from
sustained delivery when administered to treat male hypogonadism. As
used herein, the term "LPT-TU formulation" refers to an LPT
formulation comprising TU as the API. As used herein, the term
"LPT-TC formulation" refers to an LPT formulation comprising TC as
the API.
[0193] LPT-TU and LPT-TC formulations according to the present
invention may be tailored to provide, as determined by the assays
described in the Examples below, a desired in vitro release rate of
TU or TC, respectively, which is useful for characterizing
formulations and, in at least some cases, correlates with or may be
informative of testosterone plasma concentration in vivo.
Typically, the desired in vitro release rate for TU or TC is a
prolonged, steady rate of release. It is also generally desirable
that LPT-TU and LPT-TC formulations provide a low burst release
(and therefore low peak concentrations in vivo) of TU or TC,
respectively. In vitro release is highly dependent on the release
conditions (e.g., buffer, surfactants, solvents, temp, etc). As is
described in detail throughout this disclosure, various
characteristics of an LPT-TU or LPT-TC formulation may be selected
or optimized to provide a desired in vitro or in vivo release
profile.
[0194] As is described in detail throughout this disclosure, the
selection of a particle size distribution for testosterone or an
ester thereof may be influenced by, inter alia, the desired release
rate of the API and the gauge of the needle used to deliver the LPT
formulation as an injection. By way of non-limiting example, a
desired D.sub.v,50 particle size for TU in LPT-TU formulations or
for TC in LPT-TC formulations, may be between about 15 .mu.m and
about 90 .mu.m. For this reason, where an LPT-TU or LPT-TC
formulation is to be administered by a 20-gauge needle, a
D.sub.v,50 particle size of 250 .mu.m or less may be desirable, but
injectability must be balanced with the desired release profile. In
general, reducing the particle size improves injectability but also
increases the release rate and/or peak plasma concentration of the
API; by way of non-limiting example, the present inventors have
found that TU D.sub.v,50 particle sizes of about 15 .mu.m are
easily injectable, but may release too rapidly in vitro and,
therefore, may result in a peak plasma concentration in vivo above
the target range. Where an LPT-TU formulation is to be administered
by a needle with a larger gauge (i.e. smaller diameter) than a
20-gauge needle, a D.sub.v,50 particle size less than 15 .mu.m is
therefore desirable. It is to be understood that formulations
comprising pre-sized TU or TC that are then combined with a polymer
and solvent(s) and then homogenized may have a different TU
particle size in the combined formulation than in the original TU
particulate starting material.
[0195] LPT-testosterone (including related salts, esters,
complexes, prodrugs and analogs of testosterone) formulations
according to the present invention generally provide testosterone
supplementation in the eugonadal range, i.e. between about 10.4 and
about 34.7 nmol/L, or between about 3 and about 10 ng/mL, in
plasma. At least about 5%, and in some embodiments at least about
10%, and in some embodiments at least about 15%, and in some
embodiments at least about 20%, and in some embodiments at least
about 25%, and in some embodiments at least about 30%, and in some
embodiments at least about 35%, and in some embodiments at least
about 40%, and in some embodiments at least about 45%, and in some
embodiments at least about 50%, and in some embodiments at least
about 55%, and in some embodiments at least about 60%, and in some
embodiments at least about 65%, and in some embodiments at least
about 70%, and in some embodiments at least about 75%, of patients
to whom LPT-testosterone or LPT-TU or LPT-TC formulations according
to the present invention are administered will have total average
testosterone concentrations in plasma between about 3 and about 10
ng/mL. To have therapeutic efficacy while minimizing side effects,
LPT-testosterone and/or LPT-TU and/or LPT-TC formulations according
to the present invention should provide a low burst release of
testosterone, e.g. with no patients having a maximum testosterone
concentration in plasma (C.sub.max) of more than 25 ng/mL, or with
no more than 5% of patients having C.sub.max of more than 18 ng/mL,
or with at least 85% of patients having C.sub.max of no more than
15 ng/mL. LPT-testosterone and/or LPT-TU and/or LPT-TC formulations
according to the present invention can maintain these therapeutic
levels for extended periods of time as short as one week, and in
some embodiments up to about twelve months, e.g. at least about one
week, at least about two weeks, at least about three weeks, at
least about one month, at least about two months, at least about
three months, at least about four months, at least about five
months, at least about six months, or at least about seven months,
or at least about eight months, or at least about nine months, or
at least about ten months, or at least about eleven months.
[0196] Embodiments of the invention include liquid polymer
pharmaceutical compositions of testosterone or testosterone
undecanoate (or other testosterone esters, including, but not
limited to, or testosterone cypionate) and use thereof in the
treatment of androgen deficiency, in particular male hypogonadism,
by administration to a subject having androgen deficiency, such as
a male having hypogonadism in amounts and dosing schedules
described above and by routes of administration including but not
limited to subcutaneous administration, intramuscular
administration, and other forms of parenteral administration.
[0197] Various modifications of the above described invention will
be evident to those skilled in the art. It is intended that such
modifications are included within the scope of the following
claims.
[0198] The invention is illustrated by the following non-limiting
examples.
EXAMPLES
Example 1
[0199] The following example describes the preparation and test
methods for Liquid Polymer Technology (LPT) formulations comprising
testosterone undecanoate (TU) or testosterone cypionate (TC).
[0200] LPT Polymers To produce the formulations described in
Examples 2-8 below, LPT polymers, which were glycolic
acid-initiated, 75:25 poly(DL-lactide-co-.epsilon.-caprolactone)
(PDLCL) liquid polymers (i.e., polymers comprised of 75% DL-lactide
and 25% .epsilon.-caprolactone (mol:mol)), were produced using the
following methods. Specifically, to produce a 75:25
poly(DL-lactide-.epsilon.-caprolactone) liquid copolymer,
DL-lactide, .epsilon.-caprolactone, and glycolic acid (or other
suitable acid initiator) were provided in an amount calculated to
achieve the target molar composition and weight average molecular
weight. Table 1 provides exemplary amounts of the monomers and acid
initiators calculated to produce a 500 gram batch of copolymers
having various target weight average molecular weights and used
throughout the Examples. It is noted that the quantities of monomer
and initiator shown in the table are illustrative, and the exact
quantities of monomer and initiator may vary when different lots of
monomer are used, or when different acid initiators are used, and
can be calculated by one of skill in the art. Upon e-beam
irradiation, it is noted that the weight average molecular weight
of the polymer may reduce by approximately 0.1-20%, with higher
molecular weight polymers typically experiencing a larger reduction
within this range than lower molecular weight polymers; therefore,
the desired molecular weight of the polymer in the final
formulation (post-irradiation) may be different as compared to the
initial molecular weight.
TABLE-US-00001 TABLE 1 Weight Average DL-Lactide
.epsilon.-Caprolactone Glycolic Acid Molecular Weight Grams Mol
Grams Mol Grams Mol 5 kDa 316.5 2.2 83.5 0.73 32.0 0.42 10 kDa 396
2.7 104 0.91 14.5 0.19 14 kDa 194 1.4 52 0.46 3.6 0.047 15.5 kDa
475 3.3 125.3 1.1 8.9 0.12 18 kDa 395.6 2.74 104.4 0.91 5.25 0.7 22
kDa 396 2.7 104 0.91 5.05 0.66
[0201] To produce the polymers, a 500 mL 2-part glass reactor
equipped with a nitrogen inlet, an overhead stirrer with a
vacuum-capable stir guide and a vacuum outlet leading to a vacuum
trap and vacuum pump was assembled and placed in an oil bath. The
oil bath was set at 100.degree. C. and the reactor was placed under
vacuum to remove any residual moisture.
[0202] For each polymer composition, the vacuum on the reactor was
broken with nitrogen and the reactor was charged with the
prescribed amounts of DL-lactide, glycolic acid and
.epsilon.-caprolactone via a glass funnel. The stirrer was turned
to 10-50 rpm, the oil bath set to 160.degree. C., and the system
vacuum purged and back flushed with nitrogen three times. The
reactor was then left under a slight nitrogen purge.
[0203] A catalyst solution was prepared by weighing the appropriate
amount of tin(II) 2-ethylhexanaote (stannous octoate) into a 10 mL
volumetric flask and diluting to the mark with anhydrous toluene.
For all polymer compositions described in these Examples, once the
monomers had melted and the oil bath reached 160.degree. C.,
typically 5 mL of the catalyst solution was injected in an amount
calculated to achieve 0.03 wt % catalyst solution based on the
monomer weight via a syringe equipped with a 6-inch blunt tipped 20
g needle with continuous stirring. By way of example, for a 400 gm
batch of polymer, the amount of catalyst solution needed to add
0.03 wt % stannous octoate based on monomer weight was calculated
as 0.12 g (in 5 mL of toluene). For a 500 gm batch of polymer, the
amount needed to add 0.03 wt % stannous octoate based on monomer
weight was calculated as 0.15 g (in 5 mL of toluene).
[0204] After injection of the catalyst solution, the polymerization
reaction was continued for 16-18 hours. After the appropriate
reaction time, the vacuum trap was immersed in an ice bath and the
nitrogen inlet closed. Vacuum was applied slowly to the stirred
reaction mix for 4-6 hours with an ultimate vacuum of -22 to -25
in. Hg. Unreacted monomer was collected in the vacuum trap. After
the appropriate time the vacuum was discontinued, the reactor
purged with nitrogen, removed from the oil bath and the liquid
polymer poured into a metal, glass or PYREX.RTM.
(low-thermal-expansion plastic borosilicate glass) container and
cooled. Yield was approximately 85% for all polymer
compositions.
[0205] The weight average molecular weight of the polymers was
determined by gel permeation chromatography (GPC) with a refractive
index detector (e.g., Agilent 1260 Infinity Quaternary LC with
Agilent G1362A Refractive Index Detector).
[0206] LPT Formulations To produce the LPT formulations comprising
the active pharmaceutical ingredient (API), testosterone
undecanoate (TU), used in Examples 2-7, or testosterone cypionate
(TC), used in Example 8, 75:25 PDLCL LPT polymer of the indicated
weight average molecular weight (see individual experiments below)
was combined with the indicated solvent, and co-solvent (if
included), and mechanically mixed to assist in the dissolution
and/or dispersion of the solvent in the polymer.
[0207] Briefly, LPT polymer was heated to 60-115.degree. C.
(typically 80.degree. C.) and dispensed into an appropriate
container. After dispensing the LPT polymer, solvent(s) in the
prescribed amounts were added to the same container. The container
was mixed until a visually and tactilely (via interrogation with a
metal spatula) homogeneous solution was formed. This mixing was
performed on a 3-dimensional shaker/mixer (i.e., a TURBULA shaker
mixer), at 40 rpm for greater than 48 hours, or on ajar mill with
similar conditions. The LPT/solvent mixture was sometimes filtered
after dissolution using a pressure pot and compatible filter. The
resulting solution was a viscous, but flowable liquid polymer,
which was at that point a drug-free polymer/solvent
composition.
[0208] For the LPT-TU suspensions used in Examples 2-7,
testosterone undecanoate (TU) was added to the polymer/solvent
solution, and mixed into the polymer/solvent composition in the
amounts required to achieve the desired percentages as indicated in
the various experiments below, and mixed until homogenously
dispersed. Preparation of LPT-TU solutions is described in Example
7 below. In some experiments, the TU/polymer/solvent mixture was
homogenized to allow for injection through a 20 G needle. The
average particle size (D.sub.v,50) of the TU used to form these
suspensions comprised a wide range of particle sizes. To form a
suspension, the TU was mixed into the LPT/solvent and the TU
dispersed and any aggregates/clumps were broken up, for example, by
using an in-line homogenizer (e.g., IKA Magic Lab at 3,000 rpm for
not less than 10 minutes) or a drop down homogenizer (e.g., a
Silverson homogenizer at 2,000 to 3,500 rpm for not less than about
10 minutes). After incorporation of the TU into the polymer/solvent
mixture, the formulation was filled into syringes and the syringes
capped. The production of LPT-TU solution formulations is described
in Example 7.
[0209] For the LPT-TC suspensions used in Example 8, testosterone
cypionate (TC) was added to the polymer/solvent solution, and mixed
into the polymer/solvent composition in the amounts required to
achieve the desired percentages as indicated in the experiments in
Example 8, and mixed until homogenously dispersed. More
specifically, to form a suspension, the TC was mixed into the
LPT/solvent and the TC dispersed. In some experiments,
aggregates/clumps were broken up, for example, by using a drop down
homogenizer (e.g., a Silverson homogenizer at 2,500 rpm for not
less than about 10 minutes). After incorporation of the TC into the
polymer/solvent mixture, the formulation was filled into syringes
and the syringes were capped.
[0210] After production of the LPT-TU or LPT-TC formulations,
filled syringes were stored under refrigerated conditions (e.g.,
2-8.degree. C.), and for in vivo studies, the syringes were
irradiated via e-beam irradiation (or similar). For in vitro
studies, e-beam irradiation was not required and was not always
performed. Briefly, for e-beam irradiation, were packaged in a
secondary container (e.g., a foil pouch or tray pack), typically
with a desiccant/molecular sieve. A total irradiation dose of 30
kGy was administered to reach an approximate total internal dose of
25 kGy. In some experiments, an irradiation scheme of two passes at
15 kGy with a hold time of at least 1 hour at refrigerated
conditions between passes was used to control sample temperature
during irradiation.
[0211] Testosterone Undecanoate For the experiments conducted in
Examples 2-7, testosterone undecanoate was processed to have a
desired particle size distribution using one of the following
methods: (1) homogenized after formulating with the polymer and
solvent (Example 2); (2) homogenized or milled in water, then
lyophilized and added to LPT formulations (Example 4, all TU
samples except 86 .mu.m TU); (3) dry-sieved then added to LPT
formulations (Example 4, 86 .mu.m TU); or (4) jet milled, which is
a milling process that reduces the particle size of the drug by
repeated impact events between particles, and then added to LPT
formulations and homogenized to disperse (Examples 3, 5 and 6). The
particle size was determined using number-based particle size
calculation methods, volume-based particle size calculation
methods, or both methods (see Table 2A).
[0212] In a number-based particle size distribution method, the
particles were measured using microscopy, where a size was assigned
to each particle inspected. This approach builds a number
distribution, where each particle has equal weighting once the
final distribution is calculated. D.sub.10 is the value of the
particle diameter at 10% in the cumulative distribution, D.sub.50
is the value of the particle diameter at 50% in the cumulative
distribution, and D.sub.90 is the value of the particle diameter at
90% in the cumulative distribution. The number-based particle size
values for TU in the experiments described herein were determined
either prior to incorporation into the polymer/solvent, or after
the TU is incorporated into the polymer/solvent and is then further
homogenized, as indicated. Therefore, particle size values
determined prior to incorporation into the formulation may be
different, e.g., slightly higher, than those determined after
incorporation into the formulation.
[0213] In a volume-based particle size distribution method, which
is typically measured using laser diffraction analysis, the
majority of the total particle mass or volume comes from the larger
particles, and so the volume-based particle size distribution
typically results in a larger median particle size number
(D.sub.v,50) as compared to number-based methods, simply on the
basis of the distribution calculation. The D.sub.v,50 is known as
the median or the medium average of the particle size distribution
in a volume of particles; it is the particle diameter value at the
median of the cumulative distribution, wherein 50% of the volume of
the particle sample is comprised of particles having a larger
diameter than this value and 50% of the volume of the particle
sample is comprised of particles having a smaller diameter than
this value. D.sub.v,10 is the particle diameter value at which 10%
of the volume of the particle sample is comprised of smaller
diameter particles, D.sub.v,90 is the particle diameter value at
which 90% of the volume of the particle sample is comprised of
smaller diameter particles. Volume-based particle distribution can
be measured, for example, using a laser diffraction particle size
analyzer, such as Mastersizer.RTM. (Malvern Panalytical, Malvern,
Pa.). Software programs and calculations exist that are able to
convert the results from a number-based distribution analysis to a
volume-based distribution analysis and vice versa. Therefore, for
particle sizes calculated using a number-based method, a
volume-based particle size can also be estimated, and vice-versa.
Volume-based particle size distribution measurements are the
default choice for many ensemble light scattering techniques
including laser diffraction, and are commonly used in the
pharmaceutical industry (Burgess, J., Duffy, E., Etzler, F.,
Hickey, A., Particle Size Analysis: AAPS Workshop Report,
Cosponsored by the Food and Drug Administration and the United
States Pharmacopeia, AAPS Journal 2004; 6 (3) Article 20).
[0214] Table 2A shows the number-based particle size distribution
(D.sub.10, D.sub.50, and D.sub.90) and/or the volume-based particle
size distribution (D.sub.v,10, D.sub.v,50, and D.sub.v,90) for Test
Formulations 1-25 used in the in vitro and in vivo experiments
described in Examples 2-6. The particle size distribution values in
Table 2A are provided for the TU prior to incorporation of the TU
into the polymer and solvent (shown as TU API Particle Size
Distribution (PSD)). Particle size distribution values can also be
determined after the TU has been incorporated into the
polymer/solvent and then further homogenized, which is the final
formulation TU particle size.
[0215] Table 2B shows a comparison of four different test methods
(labeled T1, T2, T3 and T4) which were used to calculate the
volume-based particle size distribution of the Test Formulations
described herein. For each test method, differences in various
parameters of the protocol or equipment used are illustrated. It is
understood by one skilled in the art that differences in particle
size test methodology, including equipment make/model, settings,
and sample preparation technique, can lead to variability in the
resulting particle size determinations. This is illustrated in
Table 2C, which illustrates the differences in Dv,50 values which
have been obtained using the same material on the same instrument
with variations in settings and test conditions, with reference to
the test methods described in Table 2B. According to the present
invention, a Dv,50 value can be determined by any of the methods
described herein or otherwise known in the art and such values are
within the scope of the claimed invention.
TABLE-US-00002 TABLE 2A TU API Particle Size Distribution (PSD)
Pre-Formulation Mastersizer Microscopic (volume based) Test (number
based) Test Method Formulation # D.sub.10 D.sub.50 D.sub.90
D.sub.v, 10 D.sub.v, 50 D.sub.v, 90 from Table 2B 1 -- -- -- 16 90
470 T4 2, 11 3 4, 7, 8, 12, 14, 17 4 9 18 2 15 56 T2 21 22 5, 13,
15, 19 8 20 55 9 64 162 T1 6, 9, 10, 18 5 15 41 7 56 185 T2 23 16 1
2 4 1 6 21 T1 20 7 18 40 19 86 183 T4 24 -- -- -- 4 34 173 T2 25 --
-- -- 12 63 255 T3
TABLE-US-00003 TABLE 2B Instrument Particle Test Slurry Slurry
Circulating Bath Instrument Stir Rate Refractive Absorption Method
Method Media Fluid Sonication Sonication (rpm) Index Index T1
Rotate 2% 10 mM 90 s No 1000 1.62 0.1 in tube Tween 20 NaCl w/media
T2 Magnetic 0.2% 0.1% 240 s 120 s 2500 1.465 0.01 stirring Tween 80
Na4P2O7 (80%) T3 Magnetic 0.2% 0.1% No No 2500 1.465 0.01 stirring
Tween 80 Na4P2O7 T4 Vortex 0.2% 0.1% No 120 s 2500 1.465 0.01 Tween
80 Na4P2O7 (80%)
TABLE-US-00004 TABLE 2C Tolmar Particle Size Analysis (Dv, 50
.mu.m) Test Formulation # T1 T2 T3 T4 1, 2, 3, 11 -- -- 172 90 4,
7, 8, 12, 14, 17, 21, 22 20 15 -- -- 6, 9, 10, 18, 23 55 56 --
81
[0216] Testosterone Cypionate. For the experiments conducted in
Example 8, testosterone cypionate was used as provided by the
supplier (either Fabbrica Italiana Sineteici S.p.A. or Pfizer).
Testosterone cypionate was provided having a volume-based particle
size (Dv,50 .mu.m), as determined by Malvern, of approximately 29
.mu.m or approximately 41 .mu.m.
[0217] Production of Non-Polymeric Testosterone Undecanoate Control
Solution. For several of the Examples described herein, a
non-polymeric testosterone undecanoate control solution (also
referred to as the "non-polymeric control solution" or
"non-polymeric TU control solution") was used. To prepare this
control solution, testosterone undecanoate (TU), benzyl benzoate
(BzBz), and castor oil were combined in a 23.9/47.9/28.2
TU/BzBz/castor oil wt % ratio. The components were mixed on a
TURBULA.RTM. shaker mixer (GlenMills, N.J.) until the TU was fully
dissolved, at a mixing speed of -40 rpm for not less than 12 hours
to achieve a visually homogeneous formulation. After full
dissolution of the TU, the formulation was filtered via a 0.2 or
0.45 .mu.m filter.
[0218] In vitro Release Testing. In order to evaluate testosterone
undecanoate or testosterone cypionate release from the LPT-TU or
LPT-TC samples in vitro, a sample containing approximately 40 mg TU
or TC of each of the LPT-TU or LPT-TC formulations, respectively,
was injected into a sample holder. The sample holders were then
carefully placed into sample jars containing
temperature-equilibrated (37.degree. C.) aqueous release media (pH
8.7 50 mM TRIS, 50 mM ammonium sulfate, 1 wt %
hexadecyltrimethylammonium bromide, also known as
cetyltrimethylammonium bromide, or CTAB), and placed onto an
incubated shaker (38.5.degree. C. temperature setting and 25 rpm,
increased to 90 rpm after 60+10 minutes). Samples of the in vitro
release media were collected at specified timepoints (e.g., 1 hour
(0.04 days), 3 hours (0.13 days), 6 hours (0.25 days), 11 hours
(0.46 days), 1 day, 2 days, 4 days, 7 days, 10 days, 14 days, and
21 days), and each sample was analyzed by high performance liquid
chromatography (HPLC) for testosterone undecanoate or testosterone
cypionate content. Both the release rate (mg/day) and percent
cumulative release (%) of testosterone undecanoate or testosterone
cypionate were calculated for each time point.
[0219] Evaluation of Data For the in vitro and/or in vivo
experiments described herein, a target range, or target window, of
TU or TC release (in vitro experiments) or plasma testosterone
levels (in vivo experiments) may be referenced. For the in vitro
experiments, a target window for TU release was generally defined
using a lower release rate set at -1.1 mg/day, and an upper release
rate set at -3.6 mg/day (resulting in a median of -2.35 mg/day).
This target range was established for purposes of general
evaluation and comparison of formulations. The target in vitro
values are based on qualitative correlation between the in vitro
release rate of TU and the in vivo testosterone concentration in
plasma, when the same LPT-TU formulations were tested under in
vitro and in vivo conditions, as well as by qualitative
agreementwith an in vivo plasma testosterone target window in rats
(3-10 ng/mL), such as that used in the animal PK studies described
herein (Examples 2 and 5-7). These limits are based on the target
of 3-10 ng/mL in rats and may or may not apply to target ranges in
other animals or humans. Alternate in vitro target windows or
alternate release conditions (media, temperature, sample collection
times etc.) may be better suited when considering other animal
models or humans. These values are noted only for general
information and evaluation purposes in the in vitro assays and are
not necessarily reflected in the Figures. The target window for TC
release is generally defined in a similar manner, although the
lower and upper limits can vary somewhat. As with TU, the target
range for TC release was established for purposes of general
evaluation and comparison of formulations. Moreover, it is not
required that an LPT-TU formulation release TU solely within this
range or that an LPT-TC formulation release TC solely within this
range to be a suitable formulation according to the present
invention. For example, LPT-TU formulations that release TU more
quickly have a maximum in vitro release rate (RR.sub.max) that is
above the 3.6 mg/day mark, and/or drop below 1.1 mg/day more
quickly than other formulations may be candidates for formulations
in which a shorter duration of activity is desired and/or in which
an increased rate of drug release is desired. The same is true for
LPT-TC formulations. Such LPT formulations may be also useful with
a different API having physical characteristics similar to TU
(e.g., an API with low solubility in an aqueous environment), and
where a condition associated with such API can be treated, or
should be treated, using a formulation with a shorter duration of
action, or where a higher C.sub.max is well-tolerated or even
desirable.
[0220] For the animal PK studies described herein, a target range,
or target window, of mean plasma testosterone concentration levels
was set at between 3 and 10 ng/mL, which is approximately
equivalent to 10.4-34.7 nmol/L testosterone in plasma, and which is
based on FDA guidelines for humans, corresponding to testosterone
supplementation in the eugonadal range e.g. (see, e.g., Basaria and
Morgentaler). It should be noted that the target window is based on
acceptable human levels, and use in the alternate species in the in
vivo experiments was intended as a criteria to evaluate and compare
formulations. However, LPT formulations that result in mean
testosterone concentrations above or below this window, for shorter
or longer durations, such as formulations that have a C.sub.max
above and/or below this target range, or a concentration above
and/or below this range for any portion of the experiment, are
still considered to be useful LPT formulations and illustrative of
particular embodiments of the invention. Some formulations may have
a shorter duration of action, and these formulations may be useful,
for example, when such a shorter active window is desired, or when
using a different API having physical characteristics similar to
TU, but where a condition associated with such API can be treated,
or should be treated, using a formulation with a shorter duration
of action. As another example, formulations that remain within the
target window for a longer period of time are candidates for
formulations in which a longer and more sustained duration of
activity is desired. Some formulations may have a C.sub.max above
this target range, and these formulations may be useful, for
example, or where a higher C.sub.max is well-tolerated or even
desirable. Some formulations may have a C.sub.max below this target
range, and these formulations may be useful, for example, or where
a lower C.sub.max is efficacious or even desirable, possibly due to
adverse effects at high C.sub.max. Some formulations may have drug
concentrations above or below this target range, and these
formulations may be useful, for example, or where a higher or lower
dose is well-tolerated or even more efficacious or desirable.
Example 2
[0221] The following example provides experimental results directed
toward the development of Liquid Polymer Technology (LPT)
formulations comprising testosterone undecanoate (TU) in the form
of a suspension.
[0222] To produce an LPT formulation with favorable drug release
kinetics and depot degradation, extended release capability (e.g.,
60-90 days), and stability within target temperature ranges and
time periods, LPT formulations having different molecular weight
polymers and/or solvents were produced as described in Example 1
and are shown in Table 3. Table 3: (1) lists the composition of
each of the LPT Test Formulations with respect to the percentage by
weight of: testosterone undecanoate (TU), LPT polymer (LPT),
solvent (Sol), and co-solvent (Co-Sol); (2) provides the TU
particle size (volume-based, D.sub.v,50); (3) indicates the LPT
polymer and weight average molecular weight (Polymer, MW) of the
polymer; (4) identifies the solvent and co-solvent (if any); (5)
describes the physical form of the testosterone undecanoate in the
post-e-beam (final) formulation; (6) and provides the viscosity of
the final LPT formulation, post-e-beam irradiation.
[0223] LPT-TU Test Formulations 1-3 (Table 3) were selected for
analysis based on the preliminary evaluation of over 75 different
LPT formulations, because each of these formulations has the
following characteristics: (1) does not freeze at refrigeration
temperatures (-2-8.degree. C.); (2) is thermally stable at e-beam
temperatures of 20-45.degree. C. (i.e., TU does not substantially
change physical state in the formulation and remains in suspension
or substantially solid form); and (3) the final formulation is a
suspension. The control formulation (X) in this experiment is also
an LPT-TU suspension formulation that does not freeze at
refrigeration temperatures; however, it is not thermally stable at
e-beam temperatures; i.e., the TU dissolves into the polymer and
solvent matrix at the higher temperatures encountered during e-beam
irradiation, and then recrystallizes upon cooling to form a
recrystallized suspension, which results in a formulation having
less favorable testosterone release kinetics in vivo.
TABLE-US-00005 TABLE 3 Test Formulation TU Particle Size
Formulation TU/LPT/Sol/Co-Sol (Volume Based Polymer Co- Physical
Viscosity # (by weight %) D.sub.v, 50) (MW) Solvent Solvent State
(cP) X 20/30/50/0 N/A 75:25 PDLCL NMP -- Recrystallized 1576
(Recrystallized) (22 kDa) Suspension 1 20/30/25/25 90 .mu.m 75:25
PDLCL NMP PEG 300 Homogenized 1100 (5 kDa) Suspension 2 20/30/25/25
90 .mu.m 75:25 PDLCL NMP PEG 300 Homogenized 2070 (14 kDa)
Suspension 3 20/30/35/15 90 .mu.m 75:25 PDLCL DMSO PEG 400
Homogenized 840 (5 kDa) Suspension PDLCL =
poly(DL-lactide-co-.epsilon.-caprolactone) liquid polymer NMP =
N-Methyl-2-Pyrrolidone DMSO = Dimethyl Sulfoxide PEG 300 =
Polyethylene glycol, 300 Da PEG 400 = Polyethylene glycol, 400
Da
[0224] Test Formulations 1-3 and the Control Formulation X as shown
in Table 3 were produced as described in Example 1 and were
evaluated in an in vitro TU release test also as described in
Example 1. FIGS. 1A and 1B show the results of the in vitro release
testing of Test Formulations 1-3 (Test Formulations 1
(.box-solid.), 2 (.tangle-solidup.) and 3 (.smallcircle.)) and the
Control (X) LPT Formulation. FIG. 1A shows the TU release rate
(mg/day) and FIG. 1B shows the percentage of TU released over time
(days).
[0225] FIGS. 1A and 1B show that, as compared to the Control LPT
Formulation (X), all three LPT Test Formulations released TU more
rapidly, and FIG. 1B shows that all three formulations achieved
100% release by Day 21 of the experiment. The two formulations
comprising the lower molecular weight polymer (5 kDa, Test
Formulations 1 and 3, .box-solid. and .smallcircle., respectively)
had a faster rate of TU release and reached maximum TU release much
earlier than the formulation comprising the 14 kDa polymer (Test
Formulation 2, .tangle-solidup.). The Control LPT Formulation (X)
did not achieve 100% release by Day 21. FIG. 1A is an alternative
representation of in vitro release data, where the rate of TU
release is plotted against time. This representation of TU in vitro
release data correlates qualitatively with the in vivo testosterone
plasma concentration versus time for the same LPT-TU formulations
(see FIG. 2, discussed below). FIG. 1A shows that the maximum in
vitro release rate ("RR.sub.max") is much higher for Test
Formulations 1 and 3 than for Test Formulation 2. As used herein,
reference to RR.sub.max, or maximum release rate, in an in vitro
test, refers to the maximum (peak) in vitro release rate from the
formulation. A similar measurement is used in in vivo tests, which
is called C.sub.max. Reference to "C.sub.max" typically refers to a
pharmacokinetic measurement of rate that is the maximum (peak)
serum concentration of the drug achieved after a dose of the drug
is given, and is typically used in in vivo studies.
[0226] One can also review in vitro data such as that shown in
FIGS. 1A and 1B and elsewhere herein by referring to the T50%,
which is the time it takes to achieve 50% drug release (e.g., with
reference to FIG. 1A, one can calculate the time (day) at which 50%
of drug was released, which is a useful additional comparison,
particularly when one formulation releases drug much more quickly
and reaches 100% release much earlier, as compared to a slower
releasing formulation. FIG. 1A also shows that the TU release rate
decreases more quickly for Test Formulations 1 and 3 than for Test
Formulation 2 after reaching the point of maximum release rate. The
Control LPT Formulation released TU more slowly than the Test
Formulations for the first half of the study. These same trends for
Test Formulations 1, 2, and 3 were observed in vivo (see below,
FIG. 2), with consideration for the magnitude of C.sub.max for each
formulation, and the characteristics of the serum testosterone
concentration profiles after the point of C.sub.max.
[0227] These results indicate that modification of the LPT polymer
molecular weight can be used to influence the drug release rate
(e.g., use of a higher molecular weight polymer can be used to slow
the release rate, lower the C.sub.max (in vivo) or RR.sub.max (in
vitro), and/or extend the duration of drug release from the
formulation, whereas use of a lower molecular weight polymer can be
used to increase the release rate, increase the C.sub.max or
RR.sub.max, and/or shorten the duration of drug release from the
formulation). The results additionally showed that both NMP and
DMSO solvents, in combination with one of either PEG 300 or PEG 400
as a co-solvent, are suitable solvents for use in an LPT
formulation where the active pharmaceutical ingredient (API) is TU
or has characteristics similar to those of TU (e.g., has relatively
low solubility in aqueous media).
[0228] Test Formulations 1-3 as shown in Table 3 were also
evaluated for thermal stability, i.e., the ability to remain stable
(does not substantially change physical state (i.e., does not
undergo a phase transition) in the formulation and remains in
suspension or substantially solid form) at body temperatures (e.g.,
about 36.5.degree. C. to about 37.degree. C.) and up to e-beam
temperatures (e.g., 20-45.degree. C.). Thermal stability was
evaluated by differential scanning calorimetry (DSC). Briefly,
small samples (e.g. about 5-10 mg) of each formulation were sealed
in a 40 .mu.L aluminium pan. Samples were slowly heated on a DSC
(e.g. a Mettler Toledo TGA/DSC 2), and the temperature at which the
drug fully dissolved into solution was determined by identifying
the peak temperature of the endothermic dissolution event. FIG. 1C
shows the temperature sensitivity (thermal stability) of Test
Formulations 1-3, and shows that each formulation must be heated to
a temperature greater than 45.degree. C. for the suspended drug to
fully dissolve and form a solution. Accordingly each of Test
Formulations 1-3 is thermally stable according to the invention,
and are denoted as "Homogenized Suspension" (post-e-beam) in Table
3.
[0229] All three of the LPT-TU suspension Test Formulations 1, 2
and 3 described above were selected for additional testing in vivo.
Briefly, castrated male rats were divided into groups, which were
injected with either a control formulation or one of the LPT-TU
Test Formulations 1, 2 or 3. The control formulation in this
experiment was a non-polymeric solution of testosterone undecanoate
formulated in benzyl benzoate and castor oil. Each rat received a
single subcutaneous injection of control or test formulation
equivalent to 100 mg/kg testosterone undecanoate. Blood samples
were collected and processed for measurement of plasma testosterone
and testosterone undecanoate concentrations by liquid
chromatography/mass spectroscopy (LC/MS) at pre-dose, 30 minutes,
1, 3 and 10 hours on days 1, 4, 7, 14, 21, 28, 35, 42, 56, 70, 91
(all Test Formulations), 112, 125 (Control and Test Formulation 2
only), 140, and 154 (Test Formulation 2 only) days post dose. To
evaluate the results, a target range for testosterone release was
established between 3 ng/ml and 10 ng/ml, which is approximately
equivalent to 10.4-34.7 nmol/L testosterone in plasma and
corresponds to testosterone supplementation in the eugonadal range
for humans e.g. (see, e.g., Basaria and Morgentaler). Results of
this experiment are shown in FIG. 2 (Test Composition 1
(.box-solid.), Test Composition 2 (.tangle-solidup.), Test
Composition 3 (.smallcircle.), Non-Polymeric TU Control Solution
(.quadrature.)).
[0230] As shown in FIG. 2, Test Compositions 1 (.box-solid.) and 3
(.smallcircle.), which were formulated with the lower molecular
weight (5 kDa) LPT polymer and either the NMP/PEG 300 or the
DMSO/PEG 400 solvent systems, had a C.sub.max above the target
range shortly after injection. After Day 21, testosterone levels
fell to within the target range (.about.3-10 ng/ml) and remained
there until about day 91, after which point plasma testosterone was
no longer measured in these groups. Test Composition 2
(.tangle-solidup.), which was formulated with the 14 kDa LPT
polymer and the NMP/PEG 300 solvent system, entered the target
range at about Day 10, displaying a lower C.sub.max within the
target range, and the mean testosterone concentration remained
within the target range until Day 91, and then remained just under
the lower target limit for the remainder of the experiment (Day
154). The Non-Polymeric Control Solution of testosterone
undecanoate (.quadrature.) did not enter the target window for the
entirety of the experiment.
[0231] These results indicate that LPT formulations produced with
the higher molecular weight polymer are better candidates for
formulations in which longer term release of testosterone
undecanoate (and similar drugs) is desired, and additionally have a
lower C.sub.max than LPT formulations produced with lower molecular
weight polymers. LPT formulations produced with the lower molecular
weight polymer may be useful when a more rapid and/or shorter
duration of drug release is desired. The results additionally
showed that both NMP and DMSO solvents in combination with a PEG
co-solvent are suitable solvents for use in an LPT-TU formulation.
The NMP/PEG 300 co-solvent system was selected for further studies
described herein.
Example 3
[0232] The following example illustrates the effect of polymer
molecular weight, testosterone undecanoate particle size, and
solvent/co-solvent composition of an LPT-TU formulation on the
performance of the formulation.
[0233] Experiments were designed to evaluate the effect of three
different parameters on the performance of LPT-TU formulations
using the NMP/PEG 300 co-solvent system, as measured by in vitro
release and TU melt/dissolve temperature.
[0234] First, since the experiments described in Example 2 showed
that LPT polymers of a weight average molecular weight greater than
5 kDa extended the release of drug from the formulation and
improved the in vivo kinetics, in order to further demonstrate the
effect of polymer molecular weight on the extended release
performance of the formulations, LPT polymers having weight average
molecular weights of approximately 10 kDa (FIGS. 3A and 3B), 14 kDa
(FIGS. 3C and 3D), and 22 kDa (FIGS. 3E and 3F) were prepared.
Second, to evaluate the effect of the particle size of TU, LPT-TU
formulations were prepared in which the TU was jet milled to
achieve a particle size distribution having a D.sub.v,50
(volume-based particle distribution) of 15 .mu.m, 56 .mu.m, 64
.mu.m, or 90 .mu.m. Finally, to evaluate the effect of the amount
of the co-solvent PEG 300 in a formulation comprising the solvent
NMP, the amount of PEG 300 was varied in combination with NMP,
while maintaining the total amount of solvent in the formulation at
the same percentage.
[0235] Table 4 shows the LPT-TU formulations used in these
experiments. In all formulations, the polymer was a glycolic
acid-initiated, 75:25 poly(D,L-Lactide-co-.epsilon.-Caprolactone)
polymer as described in Example 1, with a molecular weight of 10
kDa, 14 kDa or 22 kDa, present in the formulation at 30% by weight.
All formulations used NMP as the solvent and PEG 300 as the
co-solvent, where the total amount of solvent (i.e., % NMP+% PEG
300) in the formulation remained constant at 50% by weight of the
formulation. Testosterone undecanoate of the indicated particle
size (see also Table 2A), was present in all formulations at 20% by
weight of the formulation. Test Formulations 9 and 10 are duplicate
formulations, produced as separate batches, used to establish
reproducibility in the experiment. Test Formulation 11 is is the
same as Test Formulation 2 described in Examples 1 and 2, and
results are shown here for comparison purposes. The formulations
were prepared using the methods described in Example 1, although in
this experiment, they were not homogenized nor subjected to e-beam
irradiation. The formulations were tested in an in vitro release
test, also as described in Example 1.
TABLE-US-00006 TABLE 4 TU Particle Size LPT-TU (volume based Test
Polymer % % D.sub.v, 10 D.sub.v, 50 D.sub.v, 90 Formulation # MW
NMP PEG 300 (.mu.m) (.mu.m) (.mu.m) 4 10 kDa 35 15 2 15 56 5 10 kDa
35 15 9 64 162 6 10 kDa 25 25 7 56 185 7 10 kDa 15 35 2 15 56 8 14
kDa 25 25 2 15 56 9 14 kDa 25 25 7 56 185 10 14 kDa 25 25 7 56 185
11 14 kDa 25 25 16 90 470 12 22 kDa 35 15 2 15 56 13 22 kDa 35 15 9
64 162 14 22 kDa 15 35 2 15 56 15 22 kDa 15 35 9 64 162
[0236] FIGS. 3A and 3B show the in vitro TU release rate (FIG. 3A,
mg/day) and the percentage TU released over time (FIG. 3B) for the
LPT formulations having the 10 kDa polymer (Test Formulation 4
(.box-solid.); Test Formulation 5 (.tangle-solidup.); Test
Formulation 6 (.circle-solid.); Test Formulation 7
(.diamond-solid.)). FIGS. 3C and 3D show the in vitro TU release
rate (FIG. 3C, mg/day) and the percentage TU released over time
(FIG. 3D) for the LPT formulations having the 14 kDa polymer (Test
Formulation 8 (.quadrature.); Test Formulation 9 (.smallcircle.);
Test Formulation 10 (.diamond.); Test Formulation 11 (.DELTA.)).
FIGS. 3E and 3F show the in vitro TU release rate (FIG. 3E, mg/day)
and the percentage TU released over time (FIG. 3F) for the LPT
formulations having the 22 kDa polymer (Test Formulation 12
(--X--); Test Formulation 13 (--+--); Test Formulation 14 (); Test
Formulation 15 (--.quadrature.--)).
[0237] FIGS. 4A-4F present the same data as in FIGS. 3A-3F, but
instead the formulations are grouped by particle size (D.sub.v,50)
instead of by polymer molecular weight. FIGS. 4A and 4B show the in
vitro TU release rate (FIG. 4A, mg/day) and the percentage TU
released over time (FIG. 4B) for the LPT formulations having 15
.mu.m TU (Test Formulation 4 (.box-solid.); Test Formulation 7
(.diamond-solid.); Test Formulation 8 (.quadrature.); Test
Formulation 12 (--X--); and Test Formulation 14 (). FIGS. 4C and 4D
show the in vitro TU release rate (FIG. 4C, mg/day) and the
percentage TU released over time (FIG. 4D) for the LPT formulations
having 56 .mu.m TU (Test Formulation 6 (.circle-solid.); Test
Formulation 9 (.smallcircle.); and Test Formulation 10
(.diamond.)). FIGS. 4E and 4F show the in vitro TU release rate
(FIG. 4E, mg/day) and the percentage TU released over time (FIG.
4F) for the LPT formulations having 64 or 90 .mu.m TU (Test
Formulation 5 (.tangle-solidup.); Test Formulation 11 (A); Test
Formulation 13 (--+--); and Test Formulation
15--.quadrature.--).
[0238] The results of these experiments demonstrate that the
molecular weight of the LPT polymer and the particle size can each
be used to control the rate of release of a drug in suspension in
the LPT formulations, as well as the duration of release of such a
drug from the formulations. More particularly, with respect to
molecular weight of the polymer, as shown in FIGS. 3A-3F and FIGS.
4A-4F, the weight average molecular weight of the polymer
influences the rate of release of TU from the formulation and the
duration of TU release from the formulation. By increasing the
weight average molecular weight of the polymer in the LPT
formulation, the rate of release of TU can be slowed and the
C.sub.max decreased, and the percentage of the release of TU over
time is also slowed or extended as the molecular weight increases.
For example, comparing FIGS. 3A, 3C and 3E, it can be seen that as
the molecular weight of the polymer increases, the release rate
curves generally tend to flatten even as the particle size changes,
generally lowering the C.sub.max and slowing the TU release rate
(the impact of particle size is discussed separately below). This
result is perhaps more clearly illustrated by comparing FIGS. 4A,
4C and 4E where in each figure the particle size is held constant.
Compositions formulated with the highest molecular weight polymers
generally release drug slowly earlier in the experiment, indicating
that they may have time delayed initial release of the drug.
Comparing FIGS. 3B, 3D and 3F, and again illustrated from the
perspective of holding particle size constant in FIGS. 4B, 4D and
4F, as the polymer weight average molecular weight increases, the
time in which 50% of the drug is released (T50%) also increases,
and the time necessary to release the complete payload of drug will
be generally slower
[0239] In contrast, as the weight average molecular weight of the
polymer decreases,
[0240] FIGS. 3A-3F and 4A-4F show that the rate of release of drug
from the formulation generally increases (and decreases more
rapidly), and higher release rate maxima (RR.sub.max) values are
produced. As the molecular weight of the polymer within the polymer
formulations decreases, the time in which 50% of the drug is
released (T50%) also decreases.
[0241] Therefore, the desired release rate and duration of release
of a drug having the characteristics of TU can be controlled, at
least in part, by controlling the molecular weight of the polymer
in the LPT formulation. If it is desirable to provide a formulation
with a shorter duration of release, where the release occurs more
quickly or reaches a higher RR.sub.max, then choosing a lower
molecular weight polymer is indicated by these experiments, and the
inverse is true of the higher molecular weight polymer
formulations. While these results demonstrate the effect of polymer
molecular weight on in vitro release, similar trends may be
expected for in vivo release as well.
[0242] As discussed above, the results of these experiments also
demonstrate that the particle size (or particle size distribution)
also significantly impacts the rate of release of a drug in
suspension in the LPT formulations, as well as the duration of
release of such a drug from the formulations. More specifically,
the results of the experiments shown in FIGS. 3A-3F and FIGS.
4A-4F, showed that increasing the particle size of the drug
generally decreased the rate of release of TU and lowered the
RR.sub.max. Conversely, as the particle size decreased, the TU
release rate increased and RR.sub.max values were higher and are
achieved earlier. Looking more closely at FIGS. 3A, 3C and 3E,
where the polymer molecular weight is held constant in each figure,
the impact of particle size is evident and is further illustrated
in FIGS. 4A, 4C and 4E. The formulations having TU with a
D.sub.v,50 of 15 .mu.m had a higher RR.sub.max, a more rapid
increase in TU release, which was followed by a more rapid decrease
in TU release, thus resulting in the formulations having a shorter
duration of release than those formulations that contained the
D.sub.V,50 56 .mu.m, 64 .mu.m or 90 .mu.m TU as shown in FIGS. 3B,
3D and 3F and in FIGS. 4B, 4D and 4F. In these figures,
formulations having TU with a D.sub.v,50 of 15 .mu.m had a shorter
duration of release than the formulations made with larger particle
size TU, and vice versa. The effect of particle size on TU release
from the formulation was less pronounced in the highest molecular
weight formulations (e.g., the 22 kDa formulations), where it
appeared that the polymer molecular weight influenced the rate of
release and duration of release more than the particle size. The
formulations produced with the 14 kDa polymers and TU having a
larger TU particle size (56 .mu.m, 64 .mu.m, 90 .mu.m) illustrate
the effects of controlling both molecular weight and particle size,
since these formulations release TU at a rate that transitions more
quickly into the theoretical therapeutic level than the highest
molecular weight polymers without the larger RR.sub.max "spike"
that was observed with the smaller particle sizes and lowest
molecular weight polymers, and these formulations also extended the
duration of release of drug from the formulation.
[0243] Therefore, the desired release rate and duration of release
of a drug having the characteristics of TU can be controlled, at
least in part, by controlling the particle size of the drug, and by
combining the TU particle size control with control of the polymer
molecular weight, the drug release rate and duration of release can
be further targeted or modified.
[0244] With regard to the amount of PEG 300 in the NMP/PEG 300
solvent system, the results of these experiments in FIGS. 3A-3F and
FIGS. 4A-4F showed that modification of the amount of PEG 300 in
the system did not substantially impact the TU release rate in the
formulations, although a more detailed analysis of the results
indicated that the higher PEG 300 percentages may be advantageous
(data not shown).
[0245] Finally, Test Formulations 4-10 and 12-15 as shown in Table
4 were also evaluated for thermal stability, i.e., the ability to
remain stable (does not substantially change physical state (i.e.,
does not undergo a phase transition) in the formulation and remains
in suspension or substantially solid form) at body temperatures
(e.g., about 36.5.degree. C. to about 37.degree. C.) and up to
e-beam temperatures (e.g., 20-45.degree. C.). Thermal stability was
evaluated by differential scanning calorimetry (DSC) as described
in Example 2. FIG. 4G shows the temperature sensitivity (thermal
stability) of Test Formulations 4-10 and 12-15, and shows that each
formulation must be heated to a temperature greater than 45.degree.
C. for the suspended drug to fully dissolve and form a solution.
Accordingly each of Test Formulations 4-10 and 12-15 is thermally
stable according to the invention.
[0246] Taken together, since the LPT-TU formulations having
polymers in the middle of the molecular weight range (e.g.,
.about.14 kDa) showed the most favorable release kinetics based on
release rate, RR.sub.max, and duration of release, LPT formulations
having polymers with a similar molecular weight were selected for
in vivo experiments as described in Example 5, where the impact of
TU particle size and the percentage of PEG 300 in the formulation
could be further evaluated.
Example 4
[0247] The following example describes the effect of TU particle
size on the release rate of LPT-TU formulations in vitro.
[0248] To further evaluate the effect of drug particle size on the
drug release rate of LPT suspension formulations, the following
experiments were performed. LPT formulations differing only in the
particle size of the TU were prepared as follows (see also Table
2A). In all of the formulations, the polymer was a glycolic
acid-initiated, 75:25 poly(D,L-Lactide-co-.epsilon.-Caprolactone)
polymer as described in Example 1, with a molecular weight of
.about.14 kDa, present in the formulation at 30% by weight. All
formulations contained NMP as the solvent and PEG 300 as the
co-solvent, each present at 25% by weight of the formulation (50%
total). Testosterone undecanoate (TU) was present in all
formulations at 20% by weight of the formulation, with each
formulation having a different D.sub.v,50 particle size as follows:
Test Formulation 16 (6 .mu.m TU; FIGS. 5A and 5B, .quadrature.),
Test Formulation 17 (15 .mu.m TU; FIGS. 5A and 5B, .diamond.), Test
Formulation 18 (56 .mu.m TU; FIGS. 5A and 5B, .smallcircle.), Test
Formulation 19 (64 .mu.m TU; FIGS. 5A and 5B, X), and Test
Formulation 20 (86 .mu.m TU; FIGS. 5A and 5B, .diamond-solid.).
[0249] The TU in these formulations was: (1) wet milled (6 .mu.m
TU); (2) jet-milled (15 TU, 56 .mu.m TU, and 64 .mu.m TU) or (3)
sieved through a 150 .mu.m sieve (86 .mu.m TU) to achieve the
target D.sub.v,50 particle size as described in Example 1, Table 2A
and in Table 5 below. The particle size measurements were
calculated using a volume-based particle size distribution method
on the drug substance prior to incorporation into the
polymer/solvent formulation. The formulations were prepared using
the methods described in Example 1, although in this experiment,
they were not homogenized nor subjected to e-beam irradiation. The
formulations were evaluated in an in vitro release test as
described in Example 1.
TABLE-US-00007 TABLE 5 LPT-TU Polymer TU Particle Size Test MW % %
D.sub.v, 10 D.sub.v, 50 D.sub.v, 90 Formulation # (30 wt %) NMP PEG
300 (.mu.m) (.mu.m) (.mu.m) 16 14 kDa 25 25 1 6 21 17 14 kDa 25 25
2 15 56 18 14 kDa 25 25 7 56 185 19 14 kDa 25 25 9 64 162 20 14 kDa
25 25 19 86 183
[0250] FIGS. 5A and 5B show the TU release rate (FIG. 5A) and the
percentage TU released over time (FIG. 5B) from each of the
formulations in Table 5 in an in vitro release test. FIGS. 5A and
5B show that as the median (D.sub.v,50) TU particle size increases,
the time in which 50% of the drug is released (T50%) also generally
increases, and the duration of release within the target window was
extended. The formulations with the smallest particle sizes had the
most rapid rate release rates, the highest release rate maxima
(RR.sub.max), and the shortest duration of release. The experiment
also showed that the LPT formulation containing TU having the
highest D.sub.v,50 particle size (86 .mu.m) had a substantially
slower initial rate of release than the other formulations,
indicating that it could take this formation longer to release a
meaningful amount of drug, at least with respect to TU. Therefore,
to effectively enter and remain within a therapeutic rate of
release for longer periods of time, LPT formulations with TU having
a larger D.sub.v,50, but where the D.sub.v,50 particle size is less
than 86 .mu.m, may be desirable. For formulations requiring a
shorter duration of release, and/or where more rapid spikes in
RR.sub.max (or referring to the action of formulations in vivo,
C.sub.max) or higher RR.sub.max (or C.sub.max) values are not an
issue, drugs having smaller particle sizes may be desirable.
[0251] In order to evaluate the extent to which the inclusion of
small drug particles impacts the release rate of the LPT-TU
formulations, another experiment was performed using the LPT-TU
formulation identical to Test Formulation 19 having a D.sub.v,50 of
64 .mu.m. TU having a D.sub.v,50 of 6 .mu.m TU was then titrated
into the formulation, and one formulation was prepared using only 6
.mu.m TU and none of the 64 .mu.m TU. Briefly, in this experiment,
the polymer was a glycolic acid-initiated, 75:25
poly(D,L-Lactide-co-.epsilon.-Caprolactone) polymer as described in
Example 1, with a molecular weight of .about.14 kDa, present in the
formulation at 30% by weight. The formulations contained NMP as the
solvent and PEG 300 as the co-solvent, each present at 25% by
weight of the formulation. Testosterone undecanoate (TU) having a
D.sub.v,50 particle size of 64 .mu.m and/or 6 .mu.m was present in
all formulations at a total of 20% by weight of the formulation in
the following ratios: (1) 6 .mu.m TU (100%) (FIGS. 5C and 5D,
.circle-solid.); (2) 64 .mu.m/6 .mu.m (60%/40%) (FIGS. 5C and 5D,
.DELTA.); (3) 64 .mu.m/6 .mu.m (80%/20%) (FIGS. 5C and 5D,
.diamond.); and (4) 64 .mu.m (100%) (FIGS. 5C and 5D, .box-solid.).
The formulations were tested in an in vitro release test as
described in Example 1.
[0252] FIG. 5C shows the TU release rate (mg/day) and FIG. 5D shows
the percentage of TU released over time. Surprisingly, the results
show that the titration of 6 .mu.m TU into the 64 .mu.m formulation
at levels of 20% or 40% did not have a significant effect on the
release profile of 64 .mu.m LPT-TU, although there was a very
slight trend toward slowing the initial release rate. These results
show that there is little to no effect of the inclusion of small
drug particles on the release kinetics of an LPT formulation, when
a drug having a larger D.sub.v,50 is predominant in the
formulation. However, without being bound by theory, the inventors
believe that in certain LPT formulations, small drug particle size
can be used to help to achieve rapid onset of action within the
therapeutic range.
Example 5
[0253] The following example describes in vitro and in vivo testing
of additional LPT-TU suspension formulations of the invention.
[0254] Based on the results of the experiments described in
Examples 2-4, additional LPT-TU formulations were designed. These
new Test Formulations are described in Table 6 as Test Formulations
21-25; Test Formulation 2 (see Example 2, Table 3) is provided for
comparison. In all LPT Test Formulations 21-25, the LPT polymer was
a glycolic acid-initiated, 75:25
poly(D,L-Lactide-co-.epsilon.-Caprolactone) polymer as described in
Example 1, with a molecular weight of between approximately 14 and
15.5 kDa, present in the formulation at 30% by weight. All
formulations used NMP as the solvent and PEG 300 as the co-solvent
in the amounts indicated in Table 6, to provide a total of 50% by
weight solvent in the formulation. Testosterone undecanoate of the
indicated D.sub.v,50 particle size, was present in all formulations
at 20% by weight of the formulation. The TU was jet-milled to
achieve the indicated target D.sub.v,50 particle size as described
in Example 1. The particle size measurements were calculated using
a volume-based particle size distribution method on the drug
substance prior to incorporation into the polymer/solvent
formulation. The formulations were prepared using the methods
described in Example 1, and were homogenized and subjected to
e-beam irradiation. A Non-Polymeric Control Solution of
testosterone undecanoate (C) as described in Example 1 was also
included in the in vivo experiments.
TABLE-US-00008 TABLE 6 Test TU Particle Size Formulation (volume
based) LPT Test TU/LPT/Sol/Co-Sol D.sub.v, 10 D.sub.v, 50 D.sub.v,
90 Polymer MW Co- Formulation # (by weight %) (.mu.m) (.mu.m)
(.mu.m) (kDa) Solvent Solvent 2 20/30/25/25 16 90 470 14 25% 25%
PEG NMP 300 21 20/30/15/35 2 15 56 15.5 15% 35% PEG NMP 300 22
20/30/25/25 2 15 56 15.5 25% 25% PEG NMP 300 23 20/30/25/25 7 56
185 14.2 25% 25% PEG NMP 300 24 20/30/25/25 4 34 173 14 25% 25% PEG
NMP 300 25 20/30/25/25 12 63 255 14 25% 25% PEG NMP 300 C
24/0/48/28 -- -- -- -- 48% 28% Castor BzBz Oil
[0255] In a first experiment, the results of which are shown in
FIGS. 6A and 6B, Test Formulations 21, 22 and 23 were tested in an
in vitro release test as described in Example 1. FIG. 6A shows the
TU release rate and FIG. 6B shows the percentage TU released over
time. Data for Test Formulation 2 is also shown in FIGS. 6A and 6B,
but the data is from a different experiment, where the results are
overlaid onto FIGS. 6A and 6B for comparison purposes (Test
Formulation 2 (FIGS. 6A and 6B, .circle-solid.), Test Formulation
21 (FIGS. 6A and 6B, .quadrature.), Test Formulation 22 (FIGS. 6A
and 6B, .tangle-solidup.) and Test Formulation 23 (FIGS. 6A and 6B,
.diamond.)). The results showed that as compared to Test
Formulation 2 (.circle-solid.), each of Test Formulations 21, 22
and 23 had a more rapid initial rate of release of TU, thus
suggesting a more rapid entry into a therapeutically meaningful
rate of release. All four of the formulations released TU for the
duration of the experiment. Therefore, each of Test Formulations
21, 22 and 23 were good candidates for testing in vivo.
[0256] Each of Test Formulations 21, 22 and 23 were tested in in
vivo. FIG. 7 shows the results of in vivo testing of the new LPT
formulations in rats. Briefly, castrated male rats were divided
into groups, which were injected with LPT-TU Test Formulation 21
(FIG. 7, .circle-solid.), Test Formulation 22 (FIG. 7, X) and Test
Formulation 23 (FIG. 7, .DELTA.) described in Table 6. Data from
Test Formulation 2 and the experiment described in Example 2 is
layered onto this graph for comparison purposes (FIG. 7,
.tangle-solidup.). One group of rats received a control formulation
(e.g., Non-Polymeric TU Control Solution), which in this
experiment, was a non-polymeric solution of testosterone
undecanoate formulated in benzyl benzoate and castor oil (FIG. 7,
.quadrature.)). Each rat received a single subcutaneous injection
of control or test formulation equivalent to 100 mg/kg testosterone
undecanoate. Blood samples were collected and processed for
measurement of plasma testosterone and testosterone undecanoate
concentrations by liquid chromatography/mass spectroscopy (LC/MS)
at pre-dose, 30 minutes, 1, 3, and 10 hours, and on days 1, 4, 7,
14, 20, 28, 35, 42, 56, 70, 91, 105, 119, 133, and 147 post
dose.
[0257] The results of this experiment showed that all three
formulations entered the therapeutic window more quickly than Test
Formulation 2. Injection of Test Formulation 22, which contained 15
.mu.m TU and 25% PEG 300, resulted in a C.sub.max and mean
testosterone concentration levels just above the target range for
several days before returning into the target range. Formulation 23
displayed the longest duration of mean testosterone concentration
within the target range among the Test Formulations 21-23,
remaining within the target range until almost Day 80. Test
Formulations 21 and 22 resulted in testosterone concentrations that
dropped below the minimum range prior to Day 60. The overlay of the
prior in vivo results from Example 2 using Test Formulation 2 shows
that this formulation achieved the longest performance within the
target window. Formulations 2, 22, and 23 illustrate an effect of
TU particle size on in vivo LPT-TU formulation kinetics, with
increased particle size being correlated with later entry of the
animals into the target testosterone concentration range, decreased
peak plasma testosterone concentration (C.sub.max), and extended
duration of formulation activity within the target range. This data
demonstrates that particle size can be controlled to affect in vivo
formulation kinetics, with smaller particle sizes being
advantageous when a higher C.sub.max and shorter duration are
desired, while larger particles are advantageous when a lower
C.sub.max and longer duration are desired. This data further
supports the validity of the trends observed in the in vitro
experiments, which also showed that particle size is a useful
method to control release from the LPT-TU formulation. It is
noteworthy that the in vivo response from the LPT-TU formulations
was far more sensitive than the response to the Non-Polymeric
Control, given the same (subcutaneous) route of administration, and
the same drug dose. Without being bound by theory, it is possible
that the LPT-TU delivery system is equipped to provide the desired
pharmacokinetic profile in vivo of TU, or an API such as TU, using
a reduced drug load, when compared to the Non-Polymeric
Control.
Example 6
[0258] The following example describes in vivo studies of LPT-TU
suspension formulations in a minipig animal model.
[0259] To further evaluate LPT Test Formulations described in
Example 5, two of the formulations, LPT Test Formulations 22 and
23, were injected into minipigs and the testosterone release over
time was evaluated. Briefly, six castrated male minipigs were
divided into two groups which were given Test Formulation 22 or 23.
Each minipig received a single subcutaneous injection of
approximately 18 mg/kg testosterone undecanoate. Blood samples were
collected and processed for measurement of plasma concentrations of
testosterone and testosterone undecanoate by liquid
chromatography/mass spectroscopy (LC/MS) pre-dose, at 30 minutes, 1
hour, and 3 hours post-dose, and on Days 1, 4, 7, 14, 21, 28, 35,
42, 56, 70, 91, 105, 119, 133, and 147 post injection.
[0260] FIG. 8 shows that in this experiment, the duration of
testosterone release from both formulations (Test Formulation 22
(X); Test Formulation 23 (A)) was shorter and the mean testosterone
concentrations were lower, as compared to the rat experiments shown
in Example 5 above, (i.e., the LPT formulations were not able to
reach or maintain the testosterone in the target window). Without
being bound by theory, the inventors believe that the testosterone
dosing of 18 mg/kg was not sufficiently high in the minipig animal
species. Therefore, a new experiment evaluated dose escalation of
the LPT-TU formulation in minipigs.
[0261] In this new experiment, Controls or LPT Test Formulation 24
were injected into minipigs as follows: [0262] Group A (Control
Group, FIG. 9, (.quadrature.)) received a single intramuscular
injection on Day 0 of the Non-Polymeric TU Control Solution (see
Example 1) in a dose that delivered approximately 29 mg/kg TU;
three of five animals in Group A (Control Group, FIG. 9, (X)) also
received a second intramuscular injection on Day 29 of the
Non-Polymeric TU Control Solution at 29 mg/kg TU. [0263] Group B
(data not shown due to plasma testosterone concentrations below the
limit of quantitation) received a single subcutaneous dose
(injected at multiple sites due to the volume) of the LPT
Polymer-Solvent without testosterone undecanoate (Vehicle Control).
[0264] Group C (FIG. 9, (.star-solid.)) received a single
subcutaneous injection on Day 0 of LPT Test Formulation 24 in a
dose that delivered approximately 29 mg/kg TU (1.6X dose delivered
in the experiment shown in FIG. 8) [0265] Group D (FIG. 9, ( ))
received a single subcutaneous injection on Day 0 of LPT Test
Formulation 24 in a dose that delivered approximately 58 mg/kg TU
(3.2X dose delivered in the experiment shown in FIG. 8) [0266]
Group E (FIG. 9, (.diamond.)) received a single subcutaneous dose
(injected at multiple sites due to the volume) of LPT Test
Formulation 24 in a dose that delivered approximately 116 mg/kg TU
(6.4X dose delivered in the experiment shown in FIG. 8); and [0267]
Group F (FIG. 9, ()) received a single subcutaneous dose (injected
at multiple sites due to the volume) of LPT Test Formulation 24 in
a dose that delivered approximately 232 mg/kg TU (12.8X dose
delivered in the experiment shown in FIG. 8).
[0268] Blood samples were collected and processed for measurement
of plasma testosterone and testosterone undecanoate concentrations
by liquid chromatography/mass spectroscopy (LC/MS) at pre dose, 30
minutes, 1 hour, 3 hours, and on days 1, 4, 7, 14, 21, 28, 35, 42,
56, 70, 91, 105, 119, 133, and 144 postinjection.
[0269] FIG. 9 shows the results of this study at 56 days
post-injection. The results show a dose-dependent effect of the
LPT-TU formulation. Specifically, as the dosing of TU increased,
the mean testosterone concentration entered and remained within or
above the target window sooner, the C.sub.max increased, and the
duration of the mean testosterone concentration within the target
window increased. Group C (.star-solid.), representing animals
receiving the lowest dose of TU, did not achieve mean testosterone
concentrations that entered the target window during this
experiment. Groups D ( ), E (.diamond.) and F () all entered the
target window between Days 0 and 4, with Groups D and E remaining
within the target window until about Days 35 and 42, respectively.
Group F had a C.sub.max above the target, and then returned to the
target window and remained there through at least Day 56. While
plasma concentrations in the LPT-TU treated groups begin to
decrease after .about.2-4 weeks depending on the dose, the
formulation continues to cause quantifiable increases in plasma
testosterone concentrations through at least day 56. With respect
to the non-polymeric control group, FIG. 9 shows that in order to
achieve mean testosterone concentrations within the target range
upon injection of this control, the second dose of the
Non-Polymeric TU Control Solution at Day 29 was required (FIG. 9,
compare (.quadrature.) to (x)).
Example 7
[0270] The following example describes in vitro and in vivo studies
of LPT-TU solution formulations of the present invention.
[0271] Following the preliminary design and screening of over 75
different LPT formulations described in Example 1, LPT-TU
formulations, where the TU is in solution in the formulation, were
also selected for further evaluation. Specifically, the
formulations shown in Table 7 were produced to study the effects of
various polymer molecular weights in an LPT-TU formulation that
utilizes benzyl benzoate as the solvent, which the inventors
discovered solubilizes drugs having the characteristics of
testosterone undecanoate, where the formulation is stable at both
refrigeration and e-beam temperatures. The second column in Table 7
below lists the composition of the LPT formulation with respect to
the percentage by weight of: testosterone undecanoate (TU), LPT
polymer (LPT), and solvent (Sol). The third column indicates the
LPT polymer and weight average molecular weight (MW) of the
polymer. The fourth column identifies the solvent, the fifth column
describes the physical form of the testosterone undecanoate in the
post-e-beam formulation, and the last column provides the viscosity
of the LPT formulation, post-e-beam irradiation. Viscosity of the
LPT solutions was tested using a Brookfield rheometer R/S CPS+ with
a C50-1 spindle at a sheer rate of 50 or 100 l/s. Each of test
formulations A, B, C, D and E has the following characteristics:
(1) does not freeze at refrigeration temperatures (-2-8.degree.
C.); (2) the formulation is a solution (TU is dissolved in the
solvent); and (3) the formulation is easily injected due to lower
viscosity. The Control formulation (X) in Table 7 is an LPT-TU
suspension formulation (see Example 1) and does not freeze at
refrigeration temperatures, but is also not thermally stable at
e-beam temperatures (i.e., the TU dissolves at the higher
temperatures encountered during e-beam irradiation) and therefore,
this formulation recrystallized post-e-beam irradiation.
TABLE-US-00009 TABLE 7 Formulation Test Composition Physical
Viscosity Formulation (TU/LPT/Sol) Polymer, MW Solvent State (cP) X
20/30/50 75:25 PDLCL, NMP Recrystallized 1576 22 kDa Suspension A
15/20/65 75:25 PDLCL, Benzyl Solution 130 5 kDa Benzoate B 15/20/65
75:25 PDLCL, Benzyl Solution 200 8.5 kDa Benzoate C 15/20/65 75:25
PDLCL, Benzyl Solution 190 10 kDa Benzoate D 15/20/65 75:25 PDLCL,
Benzyl Solution 270 14 kDa Benzoate E 15/20/65 75:25 PDLCL, Benzyl
Solution 500 22 kDa Benzoate
[0272] To produce the formulations shown in Table 7 above, LPT
polymers, which were glycolic acid-initiated, 75:25
DL-lactide/caprolactone (PDLCL) liquid polymers (i.e., polymers
comprised of 75% DL-lactide and 25% .epsilon.-caprolactone), were
produced using the methods described in Example 1, except that the
formulations were not homogenized, since they are solutions.
Briefly, a 75:25 PDLCL LPT polymer of the indicated weight average
molecular weight was combined with the benzyl benzoate solvent, and
mixed to assist in the dissolution and/or dispersion of the solvent
in the polymer. Complete homogenous dissolution required mixing
with a TURBULA.RTM. shaker-mixer (GlenMills, N.J.) until visually
and tactilely (via interrogation with a metal spatula) homogeneous.
The resulting solution was a viscous, but flowable liquid polymer
which was at that point a drug-free polymer/solvent composition.
Testosterone undecanoate (TU) was added to the polymer solution in
the amounts required to achieve the percentages indicated in Table
7 and mixed in a 3-dimensional shaker/mixer or jar mill at 40 rpm
for not less than 12 hours until the TU was fully dissolved and a
homogeneous solution was formed.
[0273] The control sample (X) is designated as a "recrystallized
suspension" because the TU in the formulation dissolved into the
polymer/solvent matrix during e-beam irradiation temperatures and
was then recrystallized, and so this formulation is representative
of the LPT-TU formulations which were found to exhibit slower in
vivo release as discussed in Example 2.
[0274] These LPT solution formulations were tested in an in vitro
release assay as described in Example 1. Samples of the in vitro
release media were collected at specified timepoints: 3 hours (0.13
days), 11 hours (0.46 days), 1 day, 2 day, 4 day, 7 day, 10 day, 14
day, and 21 day), and each sample was analyzed by HPLC for
testosterone undecanoate content. Both the release rate (mg/day)
and percent cumulative release (%) of testosterone undecanoate were
calculated and reported for each time point.
[0275] FIGS. 10A and 10B show the TU release rate (FIG. 10 A,
mg/day) and the percentage cumulative release of TU (FIG. 10B) from
Test Formulations A-E, as compared to the recrystallized suspension
Control LPT Formulation (Test Formulation A (.quadrature.); Test
Formulation B (.smallcircle.); Test Formulation C (.DELTA.); Test
Formulation D (.diamond-solid.); Test Formulation E (.box-solid.)
and Control Suspension (.circle-solid.)). The results showed that
the 5 kDa LPT-TU solution (Test Formulation A) reached 100% release
of TU in less than 15 days, whereas the LPT-TU solutions having a
higher weight average molecular weight (Test Formulations D and E)
released TU more slowly, and more similarly to the LPT-TU
recrystallized suspension formulation.
[0276] FIGS. 10A and 10B show that as the weight average molecular
weight of the polymer used in the LPT-TU solution formulations
decreases, the formulations release TU much more rapidly early in
the experiment and have a higher release rate maxima (RR.sub.max)
than the formulations made using the higher molecular weight
polymers. As the weight average molecular weight of the polymer
increases, the results show that the elevated RR.sub.max effects
diminish, although with increased molecular weight, the exhibit
very slow in vitro release of TU, such that the 14 KDa and 22 kDa
formulations reached only about 60% TU release by the end of the
experiment. Therefore, these results indicate that the TU release
rate and duration of release can be modified by changing the weight
average molecular weight of the polymer to achieve the desired
therapeutic effect, and that for the longest duration of release
within the target window, LPT-TU solution formulations having
polymer molecular weights in the mid-range (e.g., about 10 kDa to
about 14 kDa or slightly higher) are more suitable than those
having low molecular weights.
[0277] Test Formulation A (5 kDa polymer) was additionally tested
in vivo. Briefly, castrated male rats were divided into groups,
which were injected with LPT-TU Test
[0278] Formulation A or a control formulation (e.g., Non-Polymeric
TU Control Solution), which in this experiment, was a non-polymeric
solution of testosterone undecanoate formulated in benzyl benzoate
and castor oil. Each rat received a single subcutaneous injection
of approximately 100 mg/kg testosterone undecanoate. Blood samples
were collected and processed for measurement of plasma testosterone
concentrations by liquid chromatography/mass spectroscopy (LC/MS)
at pre-dose, 30 minutes, 1, 3, and 10 hours, and on days 1, 4, 7,
14, 21, 28, 35, 42, 56, 70, and 91 post injection. To evaluate the
results, as in prior experiments described herein, a target range
for testosterone release was established between 3 ng/ml and 10
ng/ml, which is approximately equivalent to 10.4-34.7 nmol/L
testosterone in plasma and corresponds to testosterone
supplementation in the eugonadal range in humans e.g. (see, e.g.,
Basaria and Morgentaler). Results of this experiment are shown in
FIG. 11 (Test Composition A (), Non-Polymeric TU Control Solution
(.quadrature.)).
[0279] FIG. 11 shows that administration of the LPT-TU solution
formulation comprising a 5 kDa polymer resulted in a rapid increase
in testosterone concentration initially with a high C.sub.max, and
the testosterone concentration then rapidly dropped to within the
target therapeutic range at about Day 14, remaining in the target
range through about Day 29. The Control (Non-Polymeric TU Control
Solution) was below the target range for the duration of the
experiment. Without being bound by theory, the inventors believed
that, based on the in vivo results using the 5 kDa formulation and
associated in vitro testing shown in FIGS. 10A and 10B, it would be
possible to slow the release of TU from the solution formulation in
vivo by increasing the LPT molecular weight above 5 kDa, with the
goal of decreasing the C.sub.max and extending the duration of
release.
[0280] Accordingly, Test Formulations C (10 kDa polymer) and D (14
kDa polymer) were selected for additional testing in vivo. In this
experiment, castrated male rats were divided into groups, which
were injected with a control formulation or LPT-TU Test Formulation
C (FIG. 12, (.diamond-solid.)) or D (FIG. 12, ()), the formulations
being described in Table 7. Data from Test Formulation 2
(.tangle-solidup.) and the experiment described in Example 2 is
layered onto this graph for comparison purposes. One group of rats
received the Non-Polymeric TU Control Solution described in Example
1 (i.e., a non-polymeric solution of testosterone undecanoate
formulated in benzyl benzoate and castor oil (FIG. 12,
.quadrature.)). Each rat received a single subcutaneous injection
of approximately 100 mg/kg testosterone undecanoate. Blood samples
were collected and processed for measurement of plasma testosterone
and testosterone undecanoate concentrations by liquid
chromatography/mass spectroscopy (LC/MS) at pre-dose, 30 minutes,
1, 3, and 10 hours, and on days 1, 4, 7, 14, 20, 28, 35, 42, 56,
70, 91, 105, 119, 133, and 147 post injection.
[0281] FIG. 12 shows that both of the LPT-TU solution formulations
had a C.sub.max that exceeded the target range in the first two
weeks of the experiment, although the Test Formulation D (14 kDa
polymer) had a lower C.sub.max, showing that as the polymer
molecular weight increases, the C.sub.max can be reduced. Both
formulations subsequently entered the target range, remaining there
until approximately Day 28. In comparison Test Formulation 2, which
is an LPT-TU suspension formulation of the invention, entered the
target range later than the solutions, had a much lower C.sub.max,
and had a much longer duration within the target window than the
solution formulations. These results show that these LPT solution
formulations are best utilized with drugs and/or conditions in
which a shorter duration of release is desired. In addition, the
results show that that polymer molecular weight can be utilized to
control the release of the drug from the solution formulation. For
some drugs, including those that have physical characteristics in
common with TU (e.g., low solubility in aqueous media), it may be
desirable to have faster drug release, shorter duration activity,
and/or a higher C.sub.max, and these LPT solution formulations
provide those features.
Example 8
[0282] The following example provides experimental results directed
toward the development of Liquid Polymer Technology (LPT)
formulations comprising testosterone cypionate (TC) in the form of
a suspension.
[0283] To produce an LPT formulation with favorable drug release
kinetics and depot degradation, extended release capability (e.g.,
60-90 days), and stability within target temperature ranges and
time periods, LPT formulations having different molecular weight
polymers and/or solvents were produced as described in Example 1
and are shown in Table 8. Table 8: (1) lists the composition of
each of the LPT Test Formulations with respect to the percentage by
weight of: testosterone cypionate (TC), LPT polymer (LPT), solvent
(Sol), and co-solvent (Co-Sol); (2) provides the TC particle size
(volume-based, D.sub.v,50); (3) indicates the LPT polymer and
weight average molecular weight (Polymer, MW) of the polymer; (4)
identifies the solvent and co-solvent (if any); (5) describes the
physical form of the testosterone cypionate in the (final)
formulation; (6) and provides the viscosity of the final LPT
formulation.
TABLE-US-00010 TABLE 8 Test Formulation TC Particle Size
Formulation TC/LPT/Sol/Co-Sol (Volume Based Polymer Co- Physical
Viscosity # (by weight %) D.sub.v, 50) (MW) Solvent Solvent State
(cP) 1 20/30/25/25 29 .mu.m 75:25 PDLCL NMP PEG300 Suspension 1383
(10 kDa) 2 20/30/25/25 29 .mu.m 75:25 PDLCL NMP PEG 300 Suspension
2342 (14 kDa) 3 20/30/25/25 41 .mu.m 75:25 PDLCL NMP PEG 300
Homogenized 4230 (22 kDa) Suspension 4 20/30/40/10 41 .mu.m 75:25
PDLCL NMP PEG 300 Homogenized 1538 (22 kDa) Suspension 5
20/30/25/25 41 .mu.m 75:25 PDLCL NMP PEG 300 Homogenized 8634 (33
kDa) Suspension 6 20/30/40/10 41 .mu.m 75:25 PDLCL NMP PEG 300
Homogenized 2936 (33 kDa) Suspension PDLCL =
poly(DL-lactide-co-.epsilon.-caprolactone) liquid polymer NMP =
N-Methyl-2-Pyrrolidone PEG 300 = Polyethylene glycol, 300 Da
[0284] Each of the LPT-TC Test Formulations 1-6 (Table 8) were
demonstrated to have the following characteristics: (1) does not
freeze at refrigeration temperatures (.about.2-8.degree. C.); (2)
is thermally stable at e-beam temperatures, or temperatures of
20-45.degree. C. (i.e., TC does not substantially change physical
state in the formulation and remains in suspension or substantially
solid or suspended form); and (3) the final formulation is a
suspension.
[0285] Test Formulations 1-6 as shown in Table 8 were produced as
described in Example 1 and were evaluated for thermal stability,
i.e., the ability to remain stable (does not change physical state
or undergo a phase transition, in the formulation and remains in
suspension or substantially solid form) at body temperatures (e.g.,
about 36.5.degree. C. to about 37.degree. C.) and up to e-beam
temperatures (e.g., 20-45.degree. C.). Thermal stability was
evaluated by differential scanning calorimetry (DSC). Briefly,
small samples (e.g. about 5-10 mg) of each formulation was sealed
in a 40 .mu.L aluminium pan. Samples were slowly heated on a DSC
(e.g. a Mettler Toledo TGA/DSC 2), and the temperature at which the
drug fully dissolved into solution was determined by identifying
the peak temperature of the endothermic dissolution event. FIG. 13
shows the temperature sensitivity (thermal stability) of Test
Formulations 1-6, and shows that each formulation must be heated to
a temperature greater than 45.degree. C. for the suspended drug to
fully dissolve and form a solution.
[0286] Viscosity was assessed using a cone and plate rheometer
(e.g. a Brookfield R/S CPS+) with spindle (e.g. C50-1) at various
shear rates; typically viscosity at 100 s.sup.1 is reported. Each
of Test Formulations 1, 2, 3, 4 and 6 have viscosities under 5000
cP, making them suitable for injection using a 20 G needle. Test
Formulation 5 has the highest viscosity at 8634 cP, which higher
than generally desired for a formulation of the present invention
when using a 20 G needle, unless a larger needle is used. Also, a
comparison of Test Formulation 5 with Test Formulation 6, which
differ only in the amount of PEG 300 in the formulation, shows that
the viscosity of the formulation can be easily adjusted to a more
suitable range simply by modifying the co-solvent content, while
not sacrificing thermal stability.
[0287] Test Formulations 1, 2 and 4 as shown in Table 8 were
selected for further evaluation in an in vitro TC release test also
as described in Example 1. FIGS. 14A and 14B show the results of
the in vitro release testing of Test Formulations 1, 2 and 4 (Test
Formulations 1 (.diamond-solid.), 2 (.tangle-solidup.), and 4
(.box-solid.). FIG. 14A shows the TC release rate (mg/day) and FIG.
14B shows the percentage of TC (cumulative) released over time
(days).
[0288] FIGS. 14A and 14B show that Test Formulations 1 and 2
release TC in a similar manner and relatively quickly, whereas Test
Formulation 4 releases TC more slowly than either of the other two
formulations. FIG. 14B shows that Test Formulations 1 (10 kDa
polymer) and 2 (14 kDa polymer) achieved 100% release by
approximately Day 21 of the experiment, whereas the Test
Formulation 4, comprising the higher molecular weight polymer (22
kDa), released the drug more slowly and was at about 55% release by
Day 21 and 86% release by Day 28. FIG. 14A is an alternative
representation of in vitro release data, where the rate of TC
release is plotted against time. FIG. 14A shows that the maximum in
vitro release rate ("RR.sub.max") is much higher for Test
Formulations 1 and 2 than for Test Formulation 4. As discussed
previously herein, reference to RR.sub.max, or maximum release
rate, in an in vitro test, refers to the maximum (peak) in vitro
release rate from the formulation. A similar measurement is used in
in vivo tests, which is called C.sub.max. Reference to "C.sub.max"
typically refers to a pharmacokinetic measurement of rate that is
the maximum (peak) serum concentration of the drug achieved after a
dose of the drug is given, and is typically used in in vivo
studies.
[0289] One can also review in vitro data such as that shown in
FIGS. 14A and 14B and elsewhere herein by referring to the T50%,
which is the time it takes to achieve 50% drug release (e.g., with
reference to FIG. 14B, one can calculate the time (day) at which
50% of drug was released, which is a useful additional comparison,
particularly when one formulation releases drug much more quickly
and reaches 100% release much earlier, as compared to a slower
releasing formulation. FIG. 14B shows that Test Formulations 1 and
2 reach T50% much earlier than Test Formulation 4.
[0290] These results again show that modification of the LPT
polymer molecular weight can be used to influence the drug release
rate (e.g., use of a higher molecular weight polymer can be used to
slow the release rate, lower the C.sub.max (in vivo) or RR.sub.max
(in vitro), and/or extend the duration of drug release from the
formulation, whereas use of a lower molecular weight polymer can be
used to increase the release rate, increase the C.sub.max or
RR.sub.max, and/or shorten the duration of drug release from the
formulation). The results additionally showed that NMP, in
combination with PEG 300 as a co-solvent, is a suitable solvent for
use in an LPT formulation where the active pharmaceutical
ingredient (API) is TC, which is an API with characteristics
similar to those of TU (e.g., has relatively low solubility in
aqueous media).
[0291] Various modifications of the above described invention will
be evident to those skilled in the art. It is intended that such
modifications are included within the scope of the following
claims.
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